CN1064350C - Aryl and heteroaryl alkoxynaphtalene derivatives - Google Patents

Aryl and heteroaryl alkoxynaphtalene derivatives Download PDF

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Publication number
CN1064350C
CN1064350C CN95193806A CN95193806A CN1064350C CN 1064350 C CN1064350 C CN 1064350C CN 95193806 A CN95193806 A CN 95193806A CN 95193806 A CN95193806 A CN 95193806A CN 1064350 C CN1064350 C CN 1064350C
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naphthalene
compound
ylmethoxy
methylpiperazine
methyl
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CN1151729A (en
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B·L·查纳德
K·A·德赛
H·R·小霍华德
J·E·马考
K·D·伸克
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SmithKline Beecham Ltd
Pfizer Inc
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Abstract

Compounds of the formula wherein R1, R2, R4, R23, R24, R25 and R26 are defined as in the specification. These compounds are useful psychotherapeutics and are potent serotonin (5-HT1) agonists and antagonists.

Description

Aryl and heteroaryl alkoxynaphtalene derivatives
Background of invention
The present invention relates to aryl and heteroaryl alkoxynaphtalene derivatives, relate to its preparation method and intermediate, relate to the pharmaceutical composition that contains them and their medicinal use.Compound of the present invention is serotonin 1 (5-HT 1) selective agonist and the antagonist of acceptor.They can be used for treatment or prevention 5-HT 1Migraine, depression and the other diseases of agonist or antagonist institute indication.
European patent communique 434,561 (announcement on June 26th, 1991) relates to the 7-alkyl, the 1-that alkoxyl group and hydroxyl replace (4-replaces-the 1-piperazinyl) naphthalene.These compounds are called as and can be used for treating migraine, depression, anxiety, schizophrenia, the 5-HT of anxiety and pain 1Agonist and antagonist.
European patent communique 343,050 (announcement on November 23rd, 1989) relates to that 7-replaces, halogenated and 1-(4-replaces-the 1-piperazinyl) naphthalene that methoxyl group replaces, and they can be used as 5-HT 1AThe ligands for treating agent.
Glennon etc. are at their article " 5-HT 1D5-hydroxytryptamine receptor ", ClinicalDrug Res.Dev., 22, mention among the 25-36 (1991) and can be used as 5-HT 17-methoxyl group-the 1-of part (1-piperazinyl) naphthalene.
The article of Glennon " 5-hydroxytryptamine receptor: clinical meaning (SerotoninReceptors:Clinical Implications) ", Neuroscience and BehavoralReviews, 14, 35-47 (1990) relates to the pharmacological effect relevant with 5-hydroxytryptamine receptor, comprises no appetite, and temperature regulation is cardiovascular/the ypotension effect, sleep, psychosis, anxiety, depression is felt sick, vomiting, presenile dementia, Parkinson's disease and Hang Yan Dun Shi tarantism.
To 5-HT 1The part that acceptor has a high affinity is known as has therapeutic value to treatment by the human diseases that the serotonin imbalance causes.
Summary of the invention
The present invention relates to following formula: compound and pharmaceutically acceptable salt thereof:
Figure 95193806000930
Dotted line in its Chinese style III and the V is dispensable pair of key of arbitrariness, and as dotted line R when being two key 5Do not exist;
A is 0,1 or 2;
E is 0,1 or 2;
M is the integer of 0-6;
N is the integer of 1-3;
P is the integer of 1-6;
T is the integer of 0-3;
R 2Be the substituting group and the R that on the either carbon atom of naphthalene nucleus, can form another root key 2Each appearance all be independently selected from hydrogen, fluorine, chlorine, bromine, iodine ,-CN ,-NO 2, (the C that arbitrariness replaces with 1-7 fluorine atom (preferred 1-3 fluorine atom) not essentially 1-C 6) alkyl, (the C that arbitrariness replaces with 1-7 fluorine atom (preferred 1-3 fluorine atom) not essentially 1-C 6) alkoxyl group, arbitrariness not essentially with 1-7 fluorine atom (preferred 1-3 fluorine atom) replacement-(C 1-C 6) alkylthio ,-OH ,-NR 20R 21,-CONR 20R 21With-CO 2R 20
R 3Be hydrogen, (the C that arbitrariness replaces with 1-7 fluorine atom (preferred 1-3 fluorine atom) not essentially 1-C 10) alkyl ,-(CH 2) m-aryl ,-(CH 2) m-(C 5-C 7) cycloalkyl ,-(CH 2) n-R 27,-CO 2R 20Or arbitrariness is used the (C of 1-7 fluorine atom (preferred 1-3 fluorine atom) replacement not essentially 1-C 6) alkoxyl group; Wherein said-(CH 2) mBut the described aryl moiety arbitrariness of-aromatic yl group is independently selected from R with 1-3 not essentially 2The substituting group of any replaces in the listed substituting group; And wherein said-(CH 2) m-(C 5-C 7) described (C of group of naphthene base 5-C 7) but the cycloalkyl moiety arbitrariness is independently selected from R with 1-3 not essentially 2The substituting group of any replaces in the listed substituting group;
R 4Be
R 5Be hydrogen, (the C that arbitrariness replaces with 1-7 fluorine atom (preferred 1-3 fluorine atom) not essentially 1-C 6) alkyl, (the C that-OH or arbitrariness replace with 1-7 fluorine atom (preferred 1-3 fluorine atom) not essentially 1-C 6) alkoxyl group; Wherein said (C 1-C 6But) alkyl also arbitrariness contain two keys of 1-3 root or three key not essentially;
R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17And R 18Be selected from hydrogen independently of one another, bromine, chlorine, fluorine, the aryl, (C that arbitrariness replaces with 1-7 fluorine atom (preferred 1-3 fluorine atom) not essentially 1-C 6) alkyl, (the C that arbitrariness replaces with 1-7 fluorine atom (preferred 1-3 fluorine atom) not essentially 1-C 5) alkoxyl group, (the C that arbitrariness replaces with 1-7 fluorine atom (preferred 1-3 fluorine atom) not essentially 1-C 5) alkylthio, formyl radical ,-(C=O) R 20,-CN ,-OR 20,-NR 20R 21,-NR 20SO 2R 22,-NR 20CO 2R 22,-N=C-N (CH 3) 2,-S (O) eR 20,-SO 2NR 20R 21,-NO 2, aryl, (C 1-C 6) alkylaryl ,-(C=O) OR 20The NR of ,-(C=O) 20R 21, (C 1-C 6) alkyl, (C 1-C 6) alkenyl and (C 1-C 6) alkynyl;
R 6And R 7, R 7And R 8, R 8And R 9, R 9And R 10, R 11And R 12, R 12And R 13, R 13And R 14, R 15And R 16, R 16And R 17And R 17And R 18Form 5-7 unit alkyl ring but lump together to arbitrariness, 6 yuan of aromatic rings, 5-7 unit has a N, the heteroatomic assorted alkyl ring of O or S, or 5-6 unit has 1 or 2 N, the heteroatomic hetero-aromatic ring of O or S;
R 19Be hydrogen or (C 1-C 3) alkyl;
R 20And R 21Each appearance all be hydrogen independently, (C 1-C 6) alkyl, aryl, or (C 1-C 6) alkylaryl, perhaps R 20And R 21Its arbitrary appearance all can form (C with the nitrogen-atoms that links to each other with it when being connected in same nitrogen-atoms 4-C 7) the alkyl ring;
R 22Be (C 1-C 6) alkyl, aryl, or (C 1-C 6) alkylaryl;
A, B, D, E and F are C independently of one another, N, or (C=O);
G, I, J and K are C independently of one another, N, and O, S or (C=O), condition is that every ring has an O at the most, (C=O) or S;
L and Z are C or N, wherein R independently of one another 18When being N, Z do not exist;
M is C, N or (C=O), wherein R 19When being C=O, M do not exist;
R 23And R 24Be independently selected from hydrogen, arbitrariness is not essentially with 1-7 fluorine atom, and preferred 1-3 fluorine atom replaces-(C 1-C 6) alkyl, and when p greater than 1 the time, R 23And R 24Be selected from any other R independently of one another 23Or R 24
R 25And R 26Be independently selected from hydrogen, arbitrariness is not essentially with 1-7 fluorine atom, and preferred 1-3 fluorine atom replaces-(C 1-C 6) alkyl, and when t greater than 1 the time, R 25And R 26Be selected from any other R independently of one another 25Or R 26
R 27For-OR 20,-C (=O) NR 20R 21,-C (=O) OR 20,-CN ,-NR 20C (=O) R 21,-O (C=O) R 20
Dotted line represents that two key arbitrarinesses exist not essentially; With
The aryl moiety of above-mentioned aryl and abovementioned alkyl aryl is independently selected from phenyl, naphthyl, the naphthyl that replaces and the phenyl of replacement, the naphthyl of wherein said replacement and the phenyl of replacement can be independently selected from (the C that arbitrariness replaces with 1-3 fluorine atom not essentially with 1-3 1-C 4) alkyl, halogen, hydroxyl, cyano group, the carboxamido, (C that nitro and arbitrariness replace with 1-3 fluorine atom not essentially 1-C 4) group of alkoxyl group replaces.
The invention still further relates to the pharmaceutically acceptable acid salt of formula I compound.The acid that is used for preparing the pharmaceutically acceptable salt of above-mentioned alkali cpd of the present invention is those acid that form nontoxic acid salt, promptly contains acceptable anionic salt on the pharmacology, example hydrochloric acid salt, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, acetate, lactic acid salt, Citrate trianion, acid Citrate trianion, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, mesylate, esilate, benzene sulfonate, tosilate and pamoate (promptly 1,1 '-methylene radical two (2-hydroxyl-3-naphthoate).
The invention still further relates to the base addition salt of formula I.Can be used as those chemical bases of preparation and be as the reagent of the pharmaceutically acceptable alkali salt of tart formula I compound those therewith compounds form the alkali of nontoxic alkali salt.This type of nontoxic alkali salt comprises, but be not limited to, salt from this type of pharmaceutically acceptable positively charged ion such as alkali metal cation (for example potassium and sodium) and alkaline earth metal cation (for example calcium and magnesium), ammonium salt or water-soluble amine additive salt such as N-methylglucosamine-(meglumine), and those of alkali salt of acceptable organic amine on low-level chain triacontanol ammonium and the other drug.
Be described as R 4Above member ring systems include, but not limited to pyrryl, furyl, thienyl oxazolyl ， isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazyl, 1,3,5-oxadiazole base, 1,2,4-oxadiazole base, 1,3,5-thiadiazolyl group, 1,2,4-thiadiazolyl group, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, the 1,3,5-triazines base, 1,2,5-thiadiazine base, 1,2,5-Evil thiazinyl (Oxathiazinyl), 1,2,6-Evil thiazinyl, benzoxazolyl, benzothiazolyl, benzisothiazole base, the benzoisoxazole base, benzimidazoles base, thianaphthenyl, isothianaphthene base, benzofuryl, isobenzofuran-base, benzopyranyl, pseudoindoyl, indyl, indazolyl, isoquinolyl, quinolyl, 2 base, quinoxalinyl, quinazolyl, cinnoline base and benzoxazinyl.
Preferred substituents R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17And R 18In but two arbitrarinesses are only arranged lump together and form 5-7 unit alkyl ring, 6 yuan of aryl rings have a N, the assorted alkyl ring of the heteroatomic 5-7 of O or S unit, or have 1 or 2 N, the heteroatomic 5-6 of O or S unit heteroaryl ring;
Compound of the present invention comprises all steric isomers and all optical isomers (for example R and S enantiomorph) and their racemize and the non-enantiomer mixture of formula I.Work as R 1Be the formula III, during group shown in IV or the V,
Figure 95193806001332
Preferably at R 1The R enantiomorph at the chiral carbon atom place that represents with asterisk in the ring that occurs (for example III a ', IV a ' and V a ').
Unless otherwise, the moieties of other groups (as alkoxyl group) that alkyl that this paper is related and alkenyl and this paper are related can be a straight or branched, and they also can be cyclic (cyclopropyl for example, cyclobutyl, cyclopentyl or cyclohexyl), maybe can be straight chain or side chain and contain circular part.Unless otherwise, halogen comprises fluorine, chlorine, bromine and iodine.
Preferred formula I compound comprises following:
1-{7-(5-(2-methoxyphenyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate;
1-(7-(the 5-tertiary butyl-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine hydrochloride dihydrate;
1-methyl-4-(7-(3-phenyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl) piperazine dihydrochloride semihydrate;
1-methyl-4-(7-(5-phenyl-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl) piperazine;
1-{7-(5-(3-methoxyphenyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate;
1-{7-(5-(3,5-dimethyl isoxazole-4-yl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate;
1-{7-(3-(4-methoxyphenyl)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride semihydrate;
2-(8-(1-methyl piperidine-4-yl) naphthalene-2-base oxygen base) pyrimidine;
1-methyl-4-(7-(3-phenyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl) piperidines; With
4-{7-(5-(3,5-dimethyl isoxazole-4-yl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-the 1-methyl piperidine.
Other compounds of formula I comprise following:
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) quinoline;
1-methyl-4-(7-(piperidines-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-(7-(5-chlorothiophene-2-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
1-(7-(2-(4-chloro-phenyl-) thiazole-4-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
1-methyl-4-(7-(3-pyridin-3-yl propoxy-) naphthalene-1-yl) piperazine;
6-chloro-5-(2-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base) ethyl)-1, the 3-Indolin-2-one;
1-(7-(6-fluoro-4H-benzo (1, the 3-dioxin-8-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
1-(7-(5,6-dichloropyridine-2-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
7-chloro-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen ylmethyl) quinoline;
1-(7-(2-methoxyl group-5-pyridine-2-base benzyloxy) naphthalene-1-yl) piperazine; With
1-methyl-4-(7-(1-phenyl-1H-tetrazolium-5-base oxygen base) naphthalene-1-yl) piperazine dihydrochloride;
1-methyl-4-{7-(5-(3-trifluoromethyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl } piperazine dihydrochloride;
1-{7-(5-(4-methoxyphenyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate;
1-{7-(5-(4-chloro-phenyl-)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride dihydrate;
1-7-(5-(2, the 4-dichloro benzyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate;
1-7-(3-(4-benzyl chloride base)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride semihydrate;
5-chloro-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) benzoxazole dihydrochloride hydrate;
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl)-5-trifluoromethyl benzo thiazole dihydrochloride dihydrate;
1-{7-(3-(2-methoxyphenyl)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate;
1-7-(3-(4-chloro-phenyl-)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride;
1-7-(5-(2-methoxyphenyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate;
1-(7-1-(5-(4-chloro-phenyl-)-(1,3,4 〕 oxadiazole-2-yl) oxyethyl group } naphthalene-1-yl }-4-methylpiperazine hydrochloride dihydrate;
1-{7-(3-(2-fluorophenyl)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride;
5-bromo-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) benzoxazole dihydrochloride;
6-fluoro-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) benzoxazole dihydrochloride;
6-methoxyl group-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) benzothiazole dihydrochloride;
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base) pyrimidine;
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base)-5-trifluoromethyl pyrimidine;
5-fluoro-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base) pyrimidine;
1-(7-(5-chloropyridine-2-base oxygen base) naphthalene-1-yl)-4-methylpiperazine;
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base) cigarette nitrile;
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) quinoline;
3-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base)-6-phenyl pyridazine;
1-methyl-4-(7-(4-phenyl thiophene-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-{7-(5-(4-chloro-phenyl-) thiene-3-yl-methoxyl group) naphthalene-1-yl }-the 4-methylpiperazine;
1-(7-(2-methoxyl group-6-phenylpyridine-4-ylmethoxy)-naphthalene-1-yl)-4-methylpiperazine;
1-methyl-4-(7-(2-methyl-6-phenylpyridine-4-ylmethoxy) naphthalene-1-yl) piperazine;
1-{7-(2-(2,6-lutidine-4-yl) oxyethyl group) naphthalene-1-yl }-the 4-methylpiperazine;
1-methyl-4-(7-(6-phenylpyridine-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-methyl-4-(7-(2-pyridine-2-base oxethyl) naphthalene-1-yl) piperazine;
1-methyl-4-{7-(3-(6-picoline-2-yl) propoxy-) naphthalene-1-yl } piperazine;
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl)-4-phenyl pyrimidine;
5-fluoro-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) pyrimidine;
4,6-dimethyl-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) pyrimidine;
4-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl)-2-phenyl pyrimidine;
1-methyl-4-(7-(5-phenyl thiene-3-yl-methoxyl group) naphthalene-1-yl) piperazine;
2-(8-(1-methyl piperidine-4-yl) naphthalene-2-yloxymethyl)-6-phenyl pyrazines;
2,4-dimethyl-6-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) pyrimidine;
2-methyl-4-{2-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base) ethyl } pyrimidine;
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl)-6-phenyl pyrazines;
2,3-dimethyl-5-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) pyrazine;
5-(4-chloro-phenyl-)-3-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen ylmethyl) pyridazine;
4-(4-chloro-phenyl-)-3-ethyl-6-(8-(1-methyl piperidine-4-yl) naphthalene-2-yloxymethyl) pyridazine;
5-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl)-3-phenyl pyridazine;
1-(7-(2,5-dichloro-thiophene-3-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
3-methyl-5-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) pyridazine;
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) benzoxazole;
5-methoxyl group-2-(8-(1-methyl piperidine-4-yl) naphthalene-2-yloxymethyl) benzoxazole;
2-{1-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base) ethyl } benzoxazole;
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl)-6-trifluoromethyl benzo thiazole;
6-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl)-3H-benzoxazole-2-ketone;
7-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) benzo (d) isothiazole;
6-fluoro-7-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) benzo (d 〕 isoxazole;
1-(7-(5-tertiary butyl thiene-3-yl-methoxyl group) naphthalene-1-yl)-4-methylpiperazine;
1-methyl-4-(7-(4-methyl-5-phenyl thiene-3-yl-methoxyl group) naphthalene-1-yl) piperazine;
1-methyl-4-{7-(5-(2 '-methyl diphenyl-4-yl) thiene-3-yl-methoxyl group) naphthalene-1-yl } piperazine;
1-methyl-4-(7-(5-p-methylphenyl thiophene-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-methyl-4-(7-(5-thiotolene-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-(7-(3,5-dichloro-thiophene-2-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
N-{2-(8-(1-methyl piperidine-2-yl) naphthalene-2-yloxymethyl)-5-phenyl thiene-3-yl-} ethanamide;
1-{ 7-(4-(4-chloro-phenyl-) thiophene-2-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine;
1-methyl-4-(7-(5-thiotolene-2-ylmethoxy) naphthalene-1-yl) piperidines;
1-methyl-4-(7-(1-methyl-5-phenyl-1H-pyrroles-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-methyl-4-(7-(1,4,5-trimethylammonium-1H-pyrroles-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-(7-(5-sec.-propyl-1-methyl isophthalic acid H-pyrroles-2-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
1-methyl-4-(7-(1-methyl-5-phenyl-1H-pyrroles-2-ylmethoxy) naphthalene 1-yl) piperidines;
1-{7-(5-(4-chloro-phenyl-)-1-methyl isophthalic acid H-pyrroles-3-ylmethoxy) naphthalene-1-yl }-the 4-methylpiperazine;
1-{7-(4-(2-methoxyphenyl)-1-methyl isophthalic acid H-pyrroles-2-ylmethoxy) naphthalene-1-yl }-the 4-methylpiperazine;
1-methyl-4-(7-(3-phenyl-isoxazole azoles-5-ylmethoxy) naphthalene-1-yl) piperazine;
4-{7-(3-(2,4 dichloro benzene base) isoxazole-5-base methoxyl group) naphthalene-1-yl }-the 1-methyl piperidine;
1-methyl-4-(7-(4-methyl-3-phenyl-isoxazole azoles-5-ylmethoxy) naphthalene-1-yl) piperazine;
1-methyl-4-{7-(4-(3-trifluoromethyl) thiophene-2-ylmethoxy) naphthalene-1-yl } piperazine;
1-(7-(3-Yi propyl group isoxazole-5-base methoxyl group) naphthalene-1-yl)-4-methylpiperazine;
1-{7-(3-(3-methoxyphenyl) isothiazole-5-ylmethoxy) naphthalene-1-yl }-the 4-methylpiperazine;
1-methyl-4-(7-(3-styroyl isothiazole-5-ylmethoxy) naphthalene-1-yl) piperazine;
1-methyl-4-(7-(5-phenyl isothiazole-3-ylmethoxy) naphthalene-1-yl) piperazine;
4-{7-(5-(4-chloro-phenyl-) isothiazole-3-ylmethoxy) naphthalene-1-yl }-1-sec.-propyl piperidines;
1-sec.-propyl-4-{7-(5-(3-trifluoromethyl) isoxazole-3-base methoxyl group) naphthalene-1-yl } piperazine;
1-methyl-4-{7-(1-(5-phenyl-isoxazole azoles-3-yl) oxyethyl group)-naphthalene-1-yl } piperazine;
1-methyl-4-(7-(3-methyl-2-phenyl-3H-imidazol-4 yl methoxyl group) naphthalene-1-yl) piperazine;
1-methyl-4-(7-(1-methyl-5-phenyl-1H-imidazoles-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-ethyl-4-(7-(1-phenyl-1H-imidazol-4 yl methoxyl group) naphthalene-1-yl) piperazine;
1-methyl-4-(7-(5-methyl-4-phenyl thiophene-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-{7-(2-(4-chloro-phenyl-) oxazole-5-ylmethoxy) naphthalene-1-yl }-the 4-methylpiperazine;
1-methyl-4-(4-methyl-7-(2-Ben Ji oxazole-5-ylmethoxy) naphthalene-1-yl) piperazine;
4-{7-(2-(3-chloro-phenyl-) oxazole-5-ylmethoxy) naphthalene-1-yl }-the 1-methyl piperidine;
1-(7-(uncle 2-Ding Ji oxazole-5-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
1-methyl-4-(7-(2-phenyl thiazole-5-ylmethoxy) naphthalene-1-yl) piperazine;
1-isobutyl--4-(7-(4-methyl-2-phenyl thiazole-5-ylmethoxy) naphthalene-1-yl) piperidines;
4-{7-(2-(4-methoxyphenyl) thiazole-5-ylmethoxy) naphthalene-1-yl } piperazine-1-carboxylic acid, ethyl ester;
1-{7-(5-(3, the 4-dichlorophenyl) thiazol-2-yl methoxyl group) naphthalene-1-yl }-the 4-methylpiperazine;
1-(7-(5-benzyl thiazol-2-yl methoxyl group) naphthalene-1-yl)-4-methylpiperazine;
1-methyl-4-(7-(5-Dui Jia Ben Ji oxazole-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-(7-(4-tertiary butyl thiophene-2-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
1-methyl-4-(7-(4-methyl-5-Ben Ji oxazole-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-(7-(5-Yi Bing Ji oxazole-2-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
4-{7-(5-(2-methoxyphenyl) oxazole-2-ylmethoxy) naphthalene-1-yl }-the 1-methyl piperidine;
1-methyl-4-(7-(3-phenyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl) piperazine;
1-(4-chloro-7-(3-phenyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
1-7-(3-(4-chloro-phenyl-)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl }-4-cyclopropyl piperazine;
1-sec.-propyl-4-{7-(3-(2-methoxyphenyl)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl } piperazine;
1-benzyl-4-{ 7-(3-(4-trifluoromethyl)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl } piperazine;
4-(7-(3-phenyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl) piperazine-1-carboxylic acid, ethyl ester;
1-methyl-4-{ 7-(3-(2 '-methyl diphenyl-4-yl)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl } piperazine;
1-(7-(5-chloro-3,4-thioxene-2-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
4-(7-(3-cyclohexyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl)-1-methyl piperidine;
1-methyl-4-{7-(1-(3-phenyl-(1,2,4 〕 oxadiazole-5-yl) oxyethyl group) naphthalene-1-yl } piperazine;
1-methyl-4-{ 7-(2-(3-phenyl-(1,2,4 〕 oxadiazole-5-yl) oxyethyl group) naphthalene-1-yl } piperazine;
1-ethyl-4-{7-(3-(4-fluorophenyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl }-the 4-methyl piperidine;
1-methyl-4-(7-(3-phenyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl) piperidines;
1-methyl-4-(7-(3-phenyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl) piperazine;
1-methyl-4-{7-(1-(3-phenyl-(1,2,4) thiadiazoles-5-yl) oxyethyl group) naphthalene-1-yl } piperazine;
1-methyl-4-{7-(3-(4-Trifluoromethoxyphen-l)-(1,2,4) thiadiazoles-5-ylmethoxy) naphthalene-1-yl } piperidines;
1-methyl-4-(7-(4-phenyl thiophene-2-ylmethoxy) naphthalene-1-yl) piperidines;
1-{7-(3-(4-methoxyphenyl)-(1,2,4) thiadiazoles-5-ylmethoxy)-2-methylnaphthalene-1-yl }-the 4-methylpiperazine;
1-methyl-4-(7-(5-phenyl-(1,2,4) thiadiazoles-3-ylmethoxy) naphthalene-1-yl) piperazine;
1-{7-(5-(4-chloro-phenyl-)-(1,2,4) thiadiazoles-3-ylmethoxy) naphthalene-1-yl }-the 4-methylpiperazine;
1-methyl-4-(7-(5-phenyl-(1,2,4) thiadiazoles-3-ylmethoxy) naphthalene-1-yl) piperidines;
1-(7-(5-cyclopentyl-(1,2,4) thiadiazoles-3-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
2-{4-(7-(5-phenyl-(1,2,4) thiadiazoles-3-ylmethoxy) naphthalene-1-yl) piperazine-1-yl } ethanol;
1-methyl-4-(7-(5-phenyl-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl) piperazine;
1-{7-(5-(4 '-methoxyl biphenyl-4-yl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-the 4-methylpiperazine;
1-(7-(5-sec.-propyl-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
1-ethyl-4-methyl-4-(7-(5-phenyl-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl) piperidines;
1-methyl-4-(7-(5-phenyl thiene-3-yl-methoxyl group) naphthalene-1-yl) piperidines;
1-(7-(the 5-chlorobenzene is (b) thiophene-2-ylmethoxy also) naphthalene-1-yl)-4-methylpiperazine;
1-methyl-4-(7-(3-methyl benzo (b) thiophene-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-methyl-4-(7-(4,5,6,7-tetrahydro benzo (b) thiophene-2-ylmethoxy) naphthalene-1-yl) piperazine;
1-methyl-4-(7-(1-phenyl-1H-(1,2,3) triazole-4-ylmethoxy) naphthalene-1-yl) piperazine;
1-methyl-4-(7-(5-methyl isophthalic acid-phenyl-1H-(1,2,3) triazole-4-ylmethoxy) naphthalene-1-yl) piperazine;
4-{7-(1-(4-chloro-phenyl-)-1H-(1,2,3) triazole-4-ylmethoxy) naphthalene-1-yl }-the 1-methyl piperidine;
1-methyl-4-(7-(4-methyl-5-phenyl-4H-(1,2,4) triazole-3-ylmethoxy) naphthalene-1-yl) piperazine;
4-{7-(5-(4-chloro-phenyl-) thiene-3-yl-methoxyl group) naphthalene-1-yl }-the 1-methylpiperazine;
1-(7-(4,5-dimethyl-4H-(1,2,4) triazole-3-base methoxy) naphthalene-1-yl)-4-methylpiperazine;
1-methyl-4-(7-(4-methyl-5-phenyl-4H-(1,2,4) triazole-3-ylmethoxy) naphthalene-1-yl) piperidines;
1-(7-(5-benzyl-4-methyl-4H-(1,2,4) triazole-3-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine;
1-methyl-4-(7-(2-phenyl-2H-tetrazolium-5-ylmethoxy) naphthalene-1-yl) piperazine;
4-{7-(2-(4-chloro-phenyl-)-2H-tetrazolium-5-ylmethoxy) naphthalene-1-yl }-the 1-ethyl piperidine;
1-methyl-4-(7-(6-methyl-4-phenylpyridine-2-ylmethoxy) naphthalene-1-yl) piperazine;
4-(4-chloro-phenyl-)-2-(8-(1-methyl piperidine-4-yl) naphthalene-2-base oxygen ylmethyl) piperidines; With
1-(7-(4-tert .-butylpyridine-2-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine.
Other embodiments of the present invention comprise that wherein p is 1, and t is 0, and R 2, R 23, R 24It respectively is the formula I compound of hydrogen.
Other embodiments of the present invention comprise wherein R 4Be pyridine, triazole, imidazo (4,5-b) pyridine, the formula I compound of imidazoles-2-ketone (4,5-b) pyridine and benzoglyoxaline.
Other embodiments of the present invention comprise wherein R 4For being selected from 1,2,4-oxadiazole base, 1,2,4-thiadiazolyl group, 1,3,5-oxadiazole base and 1,3,5 yuan of heterocyclic formula I compounds of 5-thiadiazolyl group.
Figure 95193806002433
Q is-(CR in the formula 25R 26) tOr C=O, R 1, R 2, R 25, R 26With t as defined above.
The invention still further relates to a kind of being used for Mammals, treatment or prevention are selected from the pharmaceutical composition of following disease among the preferred mankind: hypertension, depressed, extensive anxiety disorder, phobia (agoraphobia for example, social phobia and simple phobia), catatonic syndrome after the wound, the avoidant personality is not normal, premature ejaculation, eating disorder (for example anorexia nervosa and bulimia nervosa), fat, chemical dependency (alcohol addiction for example, cocainism, heroinism, the phenylethyl barbituric acid addiction, nicotine cravings and benzodiazepines addiction), bunch the headache (Cluster headache), migraine, pain, presenile dementia, obsessive-compulsive disorder, Phobias, the memory disease is (for example dull-witted, amnesia and the hypomnesis relevant with the age), Parkinson's disease (for example Parkinson dementia, Parkinson that Antipsychotic drug is brought out and tardive dyskinesia), endocrine regulation (for example prolactin is too much), vasospasm (particularly in the brain vascular system), gastrointestinal tract disease (wherein relating to motility and secretory variation) and chronic paroxysmal hemicrania and the headache relevant with vascular disease, said composition comprises effective treatment or prevents formula I compound or its pharmaceutically acceptable salt and a kind of pharmaceutically acceptable carrier of this type of disease amount.
The invention still further relates to a kind of being used for Mammals, treatment or prevention are selected from the pharmaceutical composition of following disease among the preferred mankind, these treatment of diseases or prevention are promoted by the serotoninergic nerve conduction of enhanced: hypertension, depressed, extensive anxiety disorder, phobia (agoraphobia for example, social phobia and simple phobia), catatonic syndrome after the wound, the avoidant personality is not normal, premature ejaculation, eating disorder (for example anorexia nervosa and bulimia nervosa), fat, chemical dependency (alcohol addiction for example, cocainism, heroinism, the phenylethyl barbituric acid addiction, nicotine cravings and benzodiazepines addiction), bunch headache, migraine, pain, presenile dementia, obsessive-compulsive disorder, Phobias, memory disease (for example dull-witted, amnesia and the hypomnesis relevant) with the age, Parkinson's disease (Parkinson dementia for example, Parkinsonism that Antipsychotic drug is brought out and tardive dyskinesia), endocrine regulation (for example prolactin is too much), vasospasm (particularly in the brain vascular system), gastrointestinal tract disease (wherein relating to motility and secretory variation) and chronic paroxysmal hemicrania and the headache relevant with vascular disease, said composition comprise effective treatment or prevent formula I compound or its pharmaceutically acceptable salt and a kind of pharmaceutically acceptable carrier of this type of disease amount.
The invention still further relates to a kind of being used for Mammals, treatment or prevention are selected from the method for following disease among the preferred mankind: hypertension, depressed, extensive anxiety disorder, phobia (agoraphobia for example, social phobia and simple phobia), catatonic syndrome after the wound, the avoidant personality is not normal, premature ejaculation, eating disorder (for example anorexia nervosa and bulimia nervosa), fat, chemical dependency (alcohol addiction for example, cocainism, heroinism, the phenylethyl barbituric acid addiction, nicotine cravings and benzodiazepines addiction), bunch headache, migraine, pain, presenile dementia, obsessive-compulsive disorder, Phobias, the memory disease is (for example dull-witted, amnesia and the hypomnesis relevant with the age), Parkinson's disease (for example Parkinson dementia, Parkinsonism that Antipsychotic drug is brought out and tardive dyskinesia), endocrine regulation (for example prolactin is too much), vasospasm (particularly in the brain vascular system), gastrointestinal tract disease (wherein relating to motility and secretory variation) and chronic paroxysmal hemicrania and the headache relevant with vascular disease, this method comprises formula I compound or its pharmaceutically acceptable salt that gives effectively to treat or prevent this kind disease amount to the Mammals of treatment of this kind of needs or prevention.
The invention still further relates to a kind of being used for Mammals, treatment or prevention are selected from the method for following disease among the preferred mankind, these treatment of diseases or prevention can be promoted by the serotoninergic nerve conduction of enhanced: hypertension, depressed, extensive anxiety disorder, phobia (agoraphobia for example, social phobia and simple phobia), catatonic syndrome after the wound, the avoidant personality is not normal, premature ejaculation, eating disorder (for example anorexia nervosa and bulimia nervosa), fat, chemical dependency (alcohol addiction for example, cocainism, heroinism, the phenylethyl barbituric acid addiction, nicotine cravings and benzodiazepines addiction), bunch headache, migraine, pain, presenile dementia, obsessive-compulsive disorder, Phobias, memory disease (for example dull-witted, amnesia and the hypomnesis relevant) with the age, Parkinson's disease (Parkinson dementia for example, Parkinsonism that Antipsychotic drug is brought out and tardive dyskinesia), endocrine regulation (for example prolactin is too much), vasospasm (particularly in the brain vascular system), gastrointestinal tract disease (wherein relating to motility and secretory variation) and chronic paroxysmal hemicrania and the headache relevant with vascular disease, this method comprise to the Mammals of treatment of this kind of needs or prevention to be bestowed effective treatment or prevents formula I compound or its pharmaceutically acceptable salt of this type of disease amount.
The invention still further relates to a kind of being used for Mammals, treatment or prevention are selected from the pharmaceutical composition of following disease among the preferred mankind: hypertension, depressed, extensive anxiety disorder, phobia (agoraphobia for example, social phobia and simple phobia), catatonic syndrome after the wound, the avoidant personality is not normal, premature ejaculation, eating disorder (for example anorexia nervosa and bulimia nervosa), fat, chemical dependency (alcohol addiction for example, cocainism, heroinism, the phenylethyl barbituric acid addiction, nicotine cravings and benzodiazepines addiction), bunch headache, migraine, pain, presenile dementia, obsessive-compulsive disorder, Phobias, the memory disease is (for example dull-witted, amnesia and the hypomnesis relevant with the age), Parkinson's disease (for example Parkinson dementia, Parkinsonism that Antipsychotic drug is brought out and tardive dyskinesia), endocrine regulation (for example prolactin is too much), vasospasm (particularly in the brain vascular system), gastrointestinal tract disease (wherein relating to motility and secretory variation) and chronic paroxysmal hemicrania and the headache relevant with vascular disease, said composition comprises can effectively be resisted or formula I compound or its pharmaceutically acceptable salt and a kind of pharmaceutically acceptable carrier of exciting 5-hydroxytryptamine receptor amount.
The invention still further relates to a kind of being used for Mammals, treatment or prevention are selected from the pharmaceutical composition of following disease among the preferred mankind, these treatment of diseases or prevention are promoted by the serotoninergic nerve conduction of enhanced: hypertension, depressed, extensive anxiety disorder, phobia (agoraphobia for example, social phobia and simple phobia), catatonic syndrome after the wound, the avoidant personality is not normal, premature ejaculation, eating disorder (for example anorexia nervosa and bulimia nervosa), fat, chemical dependency (alcohol addiction for example, cocainism, heroinism, the phenylethyl barbituric acid addiction, nicotine cravings and benzodiazepines addiction), bunch headache, migraine, pain, presenile dementia, obsessive-compulsive disorder, Phobias, memory disease (for example dull-witted, amnesia and the hypomnesis relevant) with the age, Parkinson's disease (Parkinson dementia for example, Parkinsonism that Antipsychotic drug is brought out and tardive dyskinesia), endocrine regulation (for example prolactin is too much), vasospasm (particularly in the brain vascular system), gastrointestinal tract disease (wherein relating to motility and secretory variation) and chronic paroxysmal hemicrania and the headache relevant with vascular disease, said composition comprise and can effectively resist or formula I compound or its pharmaceutically acceptable salt and a kind of pharmaceutically acceptable carrier of exciting 5-hydroxytryptamine receptor amount.
The invention still further relates to a kind of being used for Mammals, treatment or prevention are selected from the method for following disease among the preferred mankind: hypertension, depressed, extensive anxiety disorder, phobia (agoraphobia for example, social phobia and simple phobia), catatonic syndrome after the wound, the avoidant personality is not normal, premature ejaculation, eating disorder (for example anorexia nervosa and bulimia nervosa), fat, chemical dependency (alcohol addiction for example, cocainism, heroinism, the phenylethyl barbituric acid addiction, nicotine cravings and benzodiazepines addiction), bunch headache, migraine, pain, presenile dementia, obsessive-compulsive disorder, Phobias, the memory disease is (for example dull-witted, amnesia and the hypomnesis relevant with the age), Parkinson's disease (for example Parkinson dementia, Parkinsonism that Antipsychotic drug is brought out and tardive dyskinesia), endocrine regulation (for example prolactin is too much), vasospasm (particularly in the brain vascular system), gastrointestinal tract disease (wherein relating to motility and secretory variation) and chronic paroxysmal hemicrania and the headache relevant with vascular disease, this method comprises bestowing to the Mammals of treatment of this kind of needs or prevention can effectively be resisted or formula I compound or its pharmaceutically acceptable salt of exciting 5-hydroxytryptamine receptor amount.
The invention still further relates to a kind of being used for Mammals, treatment or prevention are selected from the method for following disease among the preferred mankind, these treatment of diseases or prevention are promoted by the serotoninergic nerve conduction of enhanced: hypertension, depressed, extensive anxiety disorder, phobia (agoraphobia for example, social phobia and simple phobia), catatonic syndrome after the wound, the avoidant personality is not normal, premature ejaculation, eating disorder (for example anorexia nervosa and bulimia nervosa), fat, chemical dependency (alcohol addiction for example, cocainism, heroinism, the phenylethyl barbituric acid addiction, nicotine cravings and benzodiazepines addiction), bunch headache, migraine, pain, presenile dementia, obsessive-compulsive disorder, Phobias, memory disease (for example dull-witted, amnesia and the hypomnesis relevant) with the age, Parkinson's disease (Parkinson dementia for example, Parkinsonism that Antipsychotic drug is brought out and tardive dyskinesia), endocrine regulation (for example prolactin is too much), vasospasm (particularly in the brain vascular system), gastrointestinal tract disease (wherein relating to motility and secretory variation) and chronic paroxysmal hemicrania and the headache relevant with vascular disease, this method comprise bestowing to the Mammals of treatment of this kind of needs or prevention and can effectively resist or formula I compound or its pharmaceutically acceptable salt of exciting 5-hydroxytryptamine receptor amount.
The present invention relates to a kind of being used for Mammals, treatment or prophylactic pharmaceutical composition among the preferred mankind, these treatment of diseases or prevention promote that by the serotoninergic nerve conduction of enhanced said composition comprises
A) a kind of pharmaceutically acceptable carrier;
B) a kind of formula I compound or its pharmaceutically acceptable salt; With
C) a kind of 5-HT reuptake inhibitor, preferred Sertraline, or its pharmaceutically acceptable salt;
Wherein the amount of each activeconstituents (being formula I compound and 5-HT reuptake inhibitor) should make this combination can effectively treat or prevent this disease.
The invention still further relates to a kind of being used for Mammals, treatment or prophylactic method among the preferred mankind, these diseases are promoted that by the serotoninergic nerve conduction of enhanced this method comprises to the described Mammals of treatment of this kind of needs or prevention to be bestowed:
A) a kind of formula I compound defined above or its pharmaceutically acceptable salt; With
B) a kind of 5-HT reuptake inhibitor, preferred Sertraline, or its pharmaceutically acceptable salt;
Wherein the amount of each activeconstituents (being formula I compound and 5-HT reuptake inhibitor) should make this combination can effectively treat or prevent this disease.
This paper employed " the serotoninergic nerve conduction of enhanced " refers to increase or improves the neurocyte process, thereby discharges serotonin by preceding associational cells and cynapse cross-over connection (cross) is irritated or suppress the back associational cells when being excited.
" chemical dependency " used herein means to be had unusual sensual desires or craves for medicine, or habituation.This similar drug by various medications, comprises per os usually, non-enteron aisle, and intranasal or by sucking is applied to the individuality of infection.The dependent example of chemical of available the inventive method treatment is to alcohol, Nicotine, Cocaine, heroine, the dependency of phenylethyl barbituric acid and benzodiazepines (for example Vallium (trade mark)).This paper employed " therapeutical chemistry product dependency " refers to reduce or slow down this kind dependency.
Sertraline used herein, (1S-cis)-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-N-methyl isophthalic acid-naphthylamines has C 17H 17NCl 2Chemical formula and following structural formula:
Figure 95193806002934
Its synthetic United States Patent (USP) 4 that is described in, 536, in 518, it is useful thymoleptic and fenisorex that this patent transfers Pfizer Inc.. sertraline salts hydrochlorate, and it is depressed also to can be used for treatment, the chemical dependency, the anxiety obsessive-compulsive disorder, phobia, Phobias, catatonic syndrome and premature ejaculation after the wound.
Detailed description of the present invention
Formula I compound can and be discussed preparation by following reaction scheme.Unless refer else, reaction scheme below and in question a, e, m, n, p, t, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R 24, R 25, R 26, R 27, A, B, D, E, F, G, I, J, K, L, Z, M and O and structural formula I, II, III, IV, V, VI ', the X V, X VI and X VII are as defined above.
Figure 95193806003040
Figure 95193806003041
Figure 9519380600311
Figure 95193806003243
Reaction scheme 4
Figure 95193806003446
According to reaction scheme 1, the compound of formula I can be by the alkylation preparation to formula VI intermediate of the compound of following general formula:
R 4-(CR 23R 24) pY is leavings group such as chlorine in-the Y formula, bromine, iodine ,-OSO 2Ph ,-OSO 2PhCH 3,-OSO 2CH 3,-OSO 2CF 3(trifluoromethane sulfonyloxy) or OH.
Alkylated reaction can be at alkali such as triethylamine, yellow soda ash or potassium, and sodium bicarbonate or potassium, sodium hydride or potassium, or carry out under the existence of 4-Dimethylamino pyridine.The suitable solvent of this reaction can be selected from aprotic solvent such as ether, tetrahydrofuran (THF) (THF), 1,4-diox, chloroform (CHCl 3), methylene dichloride (CH 2Cl 2), N, dinethylformamide (DMF), N,N-dimethylacetamide, N-Methyl pyrrolidone, benzene, toluene or dimethylbenzene.This reaction can be carried out to the temperature of the boiling point (for example to DMF being about 100 ℃) of about solvent for use and about 1 to about 3 atmospheric atmospheric pressure at about 0 ℃.
This reaction in the dinethylformamide, is an alkali with the sodium hydride preferably at N, carries out under an about 25-100 ℃ temperature and a barometric point.
In addition, formula I compound can be synthetic by formula VI compound by the Mitsunobu chemical process.According to this method, formula VI compound and alcohols, for example 2-pyrazine methyl alcohol or 4-pyrazole methanol at triphenyl phosphine and azodicarboxy acid dialkyl ester, react under preferred diethylazodicarboxylate exists.It is known in the art that Mitsunobu is reflected at, and for example is disclosed in Synthesis, 1981,1.
According to the method for reaction scheme 2, formula VI compound can be by formula VIII compound.Formula VI compound can be converted into formula I compound by the program of reaction scheme 1 then.
Formula VIII compound by with the activated form of trifluoromethanesulfonic acid (triflic acid), trifluoromethanesulfanhydride anhydride for example, acyl chlorides or N-phenyl trifluoromethanesulfonate methylsulfonyl imines, preferred trifluoromethanesulfanhydride anhydride, reaction and be converted into the triflate (CF of formula VII 3SO 3), wherein L is CF 3SO 3-.Usually this is reflected at alkali such as triethylamine or diisopropylethylamine, carries out under preferred triethylamine exists.This reaction can be at inert solvent such as THF or CH 2Cl 2In approximately-78 ℃ to about 25 ℃ of temperature, preferably be lower than under about 0 ℃ and carry out.This method is being known in the art, for example at J.Amer.Chem.Soc., explanation is arranged in 1987,109,5478.
Formula VII compound then can be by reacting conversion accepted way of doing sth VII compound with carbon monoxide in alcoholic solvent such as methyl alcohol in the presence of the palladium catalyst, wherein L is formula-CO 2The ester of R, R is (C in the formula 1-C 6) alkyl or benzyl.Catalyzer can be selected from those that be usually used in so-called Heck reaction (for example acid chloride, Palladous chloride, chlorination two (acetonitrile) palladium).This reaction can solvent-freely be carried out or at alcoholic solvent such as methyl alcohol, ethanol, and Virahol carries out in butanols or the benzylalcohol.What this reaction was suitable is at 20 ℃-100 ℃, carries out under preferred 60 ℃-100 ℃.The details of such reaction has explanation in document (OrganicReactions 1982,27,345).
Its L of formula is-CO 2The formula VII ester of R then useful catalyst reduction to form wherein t be 1 and R 25And R 26Methylol compound for the formula VI of hydrogen.It is that the crowd knows to person skilled in the art that ester group is reduced into methylol.Preferred this ester uses borane-tetrahydrofuran (THF) title complex to reduce in inert solvent such as THF.
T is that the method that the available those skilled in the art crowd of 1 formula VI alcohol knows is converted into other formula VI alcohol in the formula.Particularly, t is that can be converted into t in the formula by the following method be 2 formula VI compound for 1 formula VI alcohol in the formula: make methylsulfonyl chloride in this alcohol and activating group such as the triethylamine (TEA) at inert solvent such as CH 2Cl 2In the reaction and produce one wherein alcohol by CH 3SO 3-metathetical activation leavings group is handled activatory with nucleophilic reagent such as sodium cyanide or potassium then in solvent such as methyl-sulphoxide This cyano group can produce carboxylic acid in hydrolysis under the acidic conditions then.This acid can be converted into ester by the method that those skilled in the art know again.For example, this acid can be reacted in the presence of acid catalyst with the alcohol (wherein R as defined above) of formula ROH, produces ester.This ester can be that to reduce t in the accepted way of doing sth be 2 formula VI compound for the mode of 1 formula VI compound by being similar to t in this ester reduction accepted way of doing sth.
According to the method for reaction scheme 3, formula VIII compound (R in the formula 1Being piperazine) the suitable piperazine reaction of the α-Tetralone an intermediate of Sertraline of through type IX and formula X forms the enamine of formula XI, the VIII compound of an oxidation accepted way of doing sth then and preparing.
The compound of the common through type IX of the enamine of formula XI and the compound of formula X are at acid catalyst such as tosic acid or TiCl 4Existence is reacted down and is prepared.If need, byproduct of reaction water can pass through to use dried reagent such as molecular sieve or calcium sulfate, or removes from reaction effectively when forming by removing with Dean Stark trap azeotropic with reflux solvent.This reacts generally at reaction-inert solvent such as benzene, toluene, THF or CH 2Cl 2In approximately-78 ℃ to about 150 ℃ of temperature, carry out.Work as TiCl 4During as acid catalyst, temperature of reaction is preferably-78 ℃ to about 25 ℃ approximately.When using azeotropic water sepn method, temperature of reaction is preferably the boiling temperature of concrete reaction solvent.
Usually, the α-Tetralone an intermediate of Sertraline of formula IX is known in the literature or can easily be prepared by the one skilled in the art.Typical preparation is the explanation that 7-hydroxyl-α-Tetralone an intermediate of Sertraline is done; (Tetrahedron Lett.; 1981; 22; 603) α of other formula IX-Tetralone an intermediate of Sertraline uses herein and synthesizes works such as Organic Synthesis in standard; Wiley, the alkylation described in the New York, acidylate and organometallic reaction easily prepare.The commercially available currently known methods preparation that maybe can make this area of the piperazine of formula X.
The enamine of formula XI can be converted into the compound of formula VIII by method for oxidation.This reaction can use many means known in the art to carry out.In acceptable method, oxygenant be noble metal catalyst as being stated from palladium or the platinum on the gac, also have tetrachlorobenzoquinone if desired, and sulphur.Preferred oxidant is the palladium that is stated from the gac.This reaction can be at reaction-inert solvent such as toluene, dimethylbenzene, THF, CH 2Cl 2, carry out in preferred toluene or the dimethylbenzene, yet solvent is always unnecessary, especially for the oxidation of carrying out with elemental sulfur.Preferred solvent is a toluene.Oxidizing reaction is carried out to about 250 ℃ of temperature at about 0 ℃ usually.Preferred oxidizing temperature depends on the concrete oxygenant of use, is about 60 ℃ to about 150 ℃ concerning the precious metal catalyst oxidation, is about 150 ℃ to about 250 ℃ concerning the sulphur oxidation, is about 0 ℃ to about 100 ℃ concerning the tetrachlorobenzoquinone oxidation.
R wherein 1Be the formula III, the formula VIII compound of IV or V group (being tetrahydropyridine, piperidines or azacycloalkyl ylmethyl) can be pressed U.S. Patent number 4,897 by 8-bromo-beta-tetrahydro naphthalenone, program or prepared by method described in the reaction scheme 4 in 405.
According to reaction scheme 4, the 8-bromo-beta-tetrahydro naphthalenone of formula X IX at first uses the described elemental sulfur oxidation of oxidation (dehydrogenation) of the enamine of oxidising agent such as top reaction scheme 3 Chinese style XI, forms the 7-hydroxyl-1-bromonaphthalene of formula X VIII.Protect hydroxyl to form formula X IV compound with suitable blocking group then.The formation of appropriate protection base and be chosen as (for example, Greene and Wuts, Protective Groups in Organic Synthesis, second edition, Wiley, New York, 1991) known to the one skilled in the art.Preferred hydroxyl protecting group is a t-butyldimethylsilyl.
After hydroxyl was protected, the naphthalene bromide of formula X IV was handled with the vinyl stannane of following formula:
Figure 95193806003848
This is handled at catalyzer as four (triphenyl phosphine) palladium ((Ph 3P) 4Pd) or three (diphenylmethylene acetone), two palladium (Pd 2(dba) 3), no ligand catalyst (Tet.Letters, 34,4243 (1991)) exists down, carries out in the Stille reaction separately or with phosphine that is added or arsine part (JACS, 113,9585 (1991)), forms wherein R 1Be III b, the formula X III compound of IV b or V b
Figure 95193806003849
The condition and the program of carrying out this reaction are known to those skilled in the art, for example at Angew.Chem.Int.Ed.Engl., in 25,508 (1986).Triflate is wherein used in the variation of this reaction, also is known in the present technique field, for example at J.Amer.Chem.Soc., in 109,5478 (1987).Alkylogen or aryl halide are wherein used in another variation of this method in the presence of CO gas and palladium catalyst, also be known, for example at J.Amer.Chem.Soc., and 110,1557 (1988).
Can remove the hydroxyl protecting group in the formula X III then, form formula VIII compound.Remove (for example, Greene and Wuts, Protective Groups in Organic Synthesis, second edition, Wiley, NewYork, 1991) known to the present technique field that the is chosen as expert of the suitable agent of protecting group and condition.
R wherein 1For the formula I compound of saturated heterocyclic (being piperidines) can use standard method known in the art, carry palladium with charcoal usually and make catalyzer, X III compound is carried out catalytic hydrogenation and prepares.R wherein 1For at the formula III a described in the summary of the invention, but the Stereoselective reduction of the formula I compound through type X III compound of the pure group of enantiomorph of IV a or V a prepares.Stereoselective reduction by with the binaphthylyl ruthenium catalyst as ((R)-2,2 1-two (diphenylphosphino)-1,1 1-binaphthylyl) the ruthenium diacetin is pressed Takaya etc. at Organic Synthesis, and 72, D.L.Coffen edits, and the method among the 74-85 (1993) is handled formula X III compound and is carried out.
In addition, the naphthalene compound of the formula X IV 1-bromo-7-hydroxyl protection of reaction scheme 4 can be used alkyl lithium reagents such as butyllithium, s-butyl lithium or tert-butyl lithium, and preferred butyllithium is handled by as follows in inert solvent.
Figure 95193806003951
Suitable solvent comprises for example ether or THF, preferred THF.Temperature of reaction is-110 ℃ to about 0 ℃ approximately.The intermediate lithium negatively charged ion of Xing Chenging can further react with suitable electrophilic reagent then thus, and R is depended in the selection of electrophilic reagent 1And R 2Locational substituting group.Being used for the suitable electrophilic reagent of compound of hydroxyl protection of preparation formula X III comprises for example carbonyl derivative or alkylating reagent such as 1-BOC-4-piperidone, 1-BOC-dried meat ammonium aldehyde (prolinal) or 1-FMOC-2-chloromethyl tetramethyleneimine.BOC is understood by present technique field those of skill in the art, refers to butoxy carbonyl.FMOC is understood by the one skilled in the art, refers to the trifluoro methoxycarbonyl.
After bromine substituent was functionalized, the program that can use one skilled in the art crowd to know was removed hydroxyl protecting group, formed wherein R 1Be tetrahydropyridine, the formula VIII compound of piperidines or azacycloalkyl ylmethyl.
Free hydroxyl group can be derived described in reaction scheme 2 then and be formed formula VI compound.
The compound of formula VIII also can prepare according to the condensation by protected or unprotected oxy-compound of formula X XI and following formula: compound of the method for reaction scheme 5: LG is Sn2 leavings group such as chlorine, bromine, iodine ,-OSO 2Ph ,-OSO 2PhCH 3,-OSO 2CH 3,-OSO 2CF 3, form the hydroxyl protection compound of formula XX.This is reflected in the inert solvent and carries out in the presence of alkali.Preferred leavings group is an iodine, and uses stoichiometric sodium or potassium iodide to prepare on the spot in reaction mixture by chlorinated derivative.Suitable solvent comprises (C 1-C 4) alcohol, methyl-sulphoxide, N, dinethylformamide, N-Methyl pyrrolidone, acetonitrile and acetone.Acetonitrile is preferred solvent.Suitable alkali comprises NaOH, KOH, triethylamine, yellow soda ash or potassium, cesium carbonate and sodium bicarbonate or potassium.Preferred alkali is sodium bicarbonate.This reaction is carried out under preferably about 70-90 ℃ of temperature generally at about 50 ℃ to about 154 ℃.
The compound of the hydroxyl protection of formula XX can be separated protection by the method that one skilled in the art crowd knows, forms formula VIII compound (for example Greene and Wuts, Protective Groups in OrganicSynthesis, second edition, Wiley, New York, 1991).Formula VIII compound can be converted into formula I compound by the method for reaction scheme 1 and 2.
R wherein 2The method that can know by one skilled in the art crowd for the formula I compound of hydrogen is by R wherein 2Other formula I compound for bromine.R wherein 2For the formula I compound of bromine can be by being similar to preparation 11 described method preparations.
Unless refer else, more than each the reaction pressure all inessential.Usually, respectively be reflected at about 1 and to about 3 normal atmosphere, carry out, preferably under environmental stress (about 1 normal atmosphere), carry out.
This can form various salt with many inorganic and organic acids as the formula I compound of alkalescence.Although this type of salt must be pharmaceutically acceptable to the administration animal, but wish usually at first from reaction mixture, to isolate formula I compound with unacceptable salt on the medicine, then the latter is handled with alkaline reagents and change into free alkali compound simply, subsequently free alkali is changed into pharmaceutically acceptable acid salt.The acid salt of alkali cpd of the present invention can be handled this alkali cpd and preparation easily by the selected inorganic or organic acid with basic equivalent in the water-containing solvent medium or in appropriate organic solvent such as methyl alcohol or ethanol.The solid salt that obtains expecting behind the careful evaporating solvent.
The acid that is used for preparing the pharmaceutically acceptable acid salt of alkali cpd of the present invention is the acid that forms the non-toxic acid additive salt, promptly contain acceptable anionic salt on the pharmacology, example hydrochloric acid salt, hydrobromate, hydriodate, nitrate, vitriol or hydrosulfate, phosphoric acid salt or acid phosphate, acetate, lactic acid salt, Citrate trianion or acid Citrate trianion, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, mesylate and pamoate (promptly 1,1 '-methylene radical two (2-hydroxyl-3-naphthoate)).
Also be tart formula I compound, for example R in essence 2Those compounds that contain carboxylate salt can form and be with acceptable cationic alkali salt on the various pharmacology.The example of this type of salt comprises basic metal or alkaline earth salt, particularly sodium salt and sylvite.These salt prepare by routine techniques.As the chemical bases of the reagent of preparation the present invention pharmaceutically acceptable alkali salt is that acidic cpd with formula I described herein forms those of nontoxic alkali salt.These nontoxic alkali salts comprise derived from such as sodium, potassium, on the pharmacology of calcium and magnesium etc. acceptable cationic those.These salt can extremely be done the gained solution evaporation then by handling corresponding acidic cpd with the acceptable cationic aqueous solution on the pharmacology that contains expectation, preferably under reduced pressure, and preparation easily.In addition, they also can obtain gained solution evaporate to dryness in the mode identical with the front then by the lower alkane alcoholic solution of acidic cpd and the alkali metal alcoholates of expectation are mixed.Under each situation, preferably use stoichiometric reagent, to guarantee to react completely and product productive rate maximum.
Formula I compound and its pharmaceutically acceptable salt (hereinafter being also referred to as " active compound ") are useful Psychotropic drugs and are effective serotonin (5-HT 1) agonist and antagonist, and can be used for treating hypertension, depression, extensive anxiety disorder, phobia (for example agoraphobia, social phobia and simple phobia), catatonic syndrome after the wound, the avoidant personality is not normal, premature ejaculation, eating disorder (for example anorexia nervosa and bulimia nervosa), obesity, chemical dependency (alcohol addiction for example, cocainism, heroinism, phenylethyl barbituric acid addiction, nicotine cravings and benzodiazepines addiction), bunch headache, migraine, pain, presenile dementia, obsessive-compulsive disorder, Phobias, the memory disease is (for example dull-witted, amnesia and the hypomnesis relevant) with the age, Parkinson's disease (for example Parkinson dementia, Parkinsonism that Antipsychotic drug is brought out and tardive dyskinesia), endocrine regulation (for example prolactin is too much), vasospasm (particularly in the brain vascular system), gastrointestinal tract disease (wherein relating to motility and secretory variation) and chronic paroxysmal hemicrania and the headache relevant with vascular disease.These compounds also can be used as vasodilator.
The compounds of this invention to the avidity of various serotonins-1 acceptor as use standard radioligand as described in the document in conjunction with test evaluation.5-HT 1AAvidity can use people's such as Hoyer method to measure (Brain Res., 1986,376,85).5-HT 1cAvidity can use people's such as Pazos method to measure (Eur.J.Pharmacol., 1985,106,539).5-HT 1DAvidity can use the method for Heuring and Peroutka to measure (J.Neurosci., 1987,7,894).
The compounds of this invention is at 5-HT 1DThe external activity of binding site can be measured according to following method.The pH that oxtail can be organized in 20 times of volumes is a homogenizing and suspending in 7.7 the damping fluid that contains 50mMTRIS hydrochloride (three (methylol) aminomethane hydrochloride).Then can be centrifugation homogenate under the 45000G 10 minutes.Abandon supernatant liquid then and with gained piller resuspending in the pH of about 20 times of volumes is 7.7 50mMTRIS hydrochloride (HCl) damping fluid.Then with this suspension 37 ℃ of down pre-cultivations 15 minutes, this suspension centrifugation 10 minutes and abandon supernatant liquid under 45000G once more afterwards.The piller that is produced (about 1g) but resuspending be 7.7 and contain 0.01% xitix, 10 μ M Pargyline and 4mMCaCl in the 150ml final pH 215mMTRIS hydrochloride (HCl) damping fluid in.Before using, this suspension keeping at least 30 minutes on ice.
Can cultivate inhibitor, contrast or vehicle as follows then.Adding 200 μ l in 50 μ l20% methyl-sulphoxide (DMSO)/80% distilled water solutions is 7.7 and contains 0.01% xitix and 10 μ M Pargylines and 4 μ M CaCl at pH 2Add the serotonine (2nM) of the tritiate in the 50mMTRIS hydrochloride damping fluid of 100mM8-hydroxyl DPAT (dipropyl amino naphthane) and 100nM mesulergine.Add 750 μ l oxtail tissues in this mixture and the suspension that is produced is rotated to guarantee even suspension.This suspension can cultivated 30 minutes in the jolting water-bath under 25 ℃ then.After cultivation was finished, suspension can use glass fibre filter (Whatman GF/B-strainer for example TM) filter.Be 7.7 50mMTRIS hydrochloride damping fluid washing piller three times with 4mlpH then.Piller placed contain 5ml scintillation solution (aquasol2 TM) scintillation vial in and place a night.Compound to each dosage calculates percent inhibition.Can calculate IC by the percent inhibition value then 50Value.
The compounds of this invention is to 5-HT 1AThe activity of binding ability can be determined as follows.Rat brain cortex organized homogenizing and be divided into many samples of 1g, with the 0.32M sucrose solution dilution of 10 times of volumes.Then can be centrifugation suspension under the 900G 10 minutes, separate supernatant liquid and centrifugation 15 minutes under 70000G again.Abandon supernatant liquor and with the piller resuspending in the pH of 10 times of volumes is 7.5 15mMTRIS hydrochloride.Suspension was cultivated 15 minutes down at 37 ℃.Pre-cultivate finish after under 70000G centrifugation suspension 15 minutes and abandon supernatant liquid.What produced organizes the piller resuspending in pH7.7 and contain 4mMCaCl 2In the 50mMTRIS hydrochloride damping fluid of 0.01% xitix.This is organized in-70 ℃ and stores down until being used for test.Melt tissue before the use immediately, dilute and remain on ice with 1 μ M Pargyline.
Then by following method cultured tissue.Prepare 50 μ l contrast, inhibitor or vehicle (1%DMSO, ultimate density) with various dosage.What add 200 μ l concentration in this solution and be 1.5nM and be dissolved in pH7.7 contains 50mMTRIS hydrochloride, 4mMCaCl 2, the tritiate DPAT in the damping fluid of 0.01% xitix and Pargyline.Add 750 μ l tissue then in this solution and with the suspension rotation that produced to guarantee homogenizing.This suspension can be cultivated 30 minutes in 37 ℃ of jolting water-baths then.Filter this solution then, with 4ml10mMpH7.5 and contain the TRIS hydrochloride washed twice of 154mMNaCl.To the compound of each dosage, contrast or vehicle calculate the percentage inhibitor.Calculate IC by the percent inhibition value 50Value.
Use aforesaid method to estimate the 5-HT of formula I compound of the present invention described in the following example 1AAnd 5-HT 1DAvidity.The IC of all test compounds 50Be lower than 0.60 μ M.
By the 5-HT of following method test The compounds of this invention to cavy 1DAntagonistic activity in the cryogenic body that agonist brings out.
Will be from Charles River, heavy 250-272g when buying, the male Hartley cavy of 300-600g is as the main body in this test during test.Cavy before test under standard laboratory conditions, supported at least 7 days in the illumination program ShiShimonoseki at 7 in the morning at 7 in afternoon.Food and water before test along with desirable.
The compounds of this invention can 1ml/kg amount with the solution administration.Used excipient changes with the compound dissolution degree.Experimental compound is generally at 5-HT 1DPer os (p.o.) administration in 60 minutes or subcutaneous (s.c.) administration in 0 minute before the agonist, this agonist is with 5.6mg/kg s.c. administration.Reading before first temperature reading, each cavy is placed in the clean plastic box for shoes that contains wood chip and metal grizzly bar floor, and makes it adapt to surrounding environment 30 minutes.Then animal is sent back in the same footwear box behind each temperature reading.Before measuring temperature, each time firmly held each animal 30 seconds with a hand.Use is carried out temperature survey with the digital temperature meter of little animal probe.This probe is made by half snappiness nylon, has the epoxy tip.This temperature probe inserts 6cm in rectum, and keeps 30 seconds or up to stable reading.Write down temperature then.
In the p.o. shaker test, " prodrug " datum temperature reading was located at-90 minutes, and test compound was located to feed at-60 minutes, read extra 30 minutes readings.In the time of 0 minute, give 5-HT then 1DAgonist, and, read temperature after 120 and 240 minutes 30,60.
In subcutaneous shaker test, prodrug datum temperature reading was located at-30 minutes.Test compound and 5-HT DAgonist feeds simultaneously, and 30,60, reads temperature after 120 and 240 minutes.
In Newman-Keuls post hoc analyzes, the variable of replicate measurement is carried out double (two-way) and analyze analytical data.
United States Patent (USP) 4,536,518 have described the synthetic of Sertraline, pharmaceutical composition and the purposes in dysthymia disorders thereof, thereby all incorporated by reference at this.The chemical formula of sertraline hydrochloride is C 17H 17NCl 2, structural formula is as follows: its synthetic United States Patent (USP) 4,536,518 that transfers Pfizer Inc. that is described in.Sertraline hydrochloride can be used as thymoleptic or fenisorex, and it is depressed also to can be used for treatment, and the chemical dependency is with anxiety diseases associated and premature ejaculation.United States Patent (USP) 4,536,518 therefore all be incorporated herein for reference.
Formula I compound can advantageously use with one or more other treatment agent, and these therapeutical agents for example are different thymoleptic, as tricyclics (amitriptyline for example, dothiepin, doxepin, Trimipramine, butriptyline, clomipramine, despramine, Mi Paming, iprindole, the Lip river is non-
Figure 95193806004453
Handkerchief is bright, nortriptyline or protriptyline), oxidase inhibitor (Isocarboxazid for example, Phenelzine or Tranylcypromine (tranylcyclopramine) or 5-HT reuptake inhibitor (fluvoxamine for example, Sertraline, fluoxetine or paroxetine), and/or use with antiparkinsonism drug, this medicine such as Dopamine HCL antiparkinsonism drug (levodopa for example, preferably with periphery decarboxylase inhibitor such as benserazide or carbidopa combination, or with dopamine agonist such as bromocriptine, the combination of methylergol carbamide or pergolide).Should understand the present invention covers and the formula I compound of one or more combination with other therapeutic agents or the use of its physiologically acceptable salt or its solvate.
The 5-HT reuptake inhibitor, preferred Sertraline is to the depression in comprising people's Mammals; The chemical dependency; Comprise Phobias, the extensive burnt chronic diseases marked by deficiency of vital energy, agoraphobia, simple phobia, catatonic syndrome is at interior anxiety disorders after social phobia and the wound; Obsessive-compulsive disorder; The avoidant personality is not normal to have positive effect with premature ejaculation, in part because the ability of the synaptosome of its blocking 5-hydroxytryptamine picked-up.
Preferably, with 5-HT reuptake inhibitor (fluvoxamine for example, Sertraline, fluoxetine or paroxetine), preferred Sertraline, or the formula I compound of its pharmaceutically acceptable salt or polymorph combination is useful Psychotropic drug and can be used for treatment or preventing disease with its pharmaceutically acceptable salt (combination of this paper Chinese style I compound and 5-HT reuptake inhibitor is referred to as " active combination "), these treatment of diseases or prevention promote (hypertension for example by the serotoninergic nerve conduction of enhanced, depressed, extensive anxiety disorder, phobia, catatonic syndrome after the wound, the avoidant personality is not normal, sexual disorder, eating disorder, fat, the chemical dependency, bunch headache, migraine, pain, presenile dementia, obsessive-compulsive disorder, Phobias, the memory disease is (for example dull-witted, amnesia and the hypomnesis relevant) with the age, Parkinson's disease (for example Parkinson dementia, parkinsonism that Antipsychotic drug is brought out and tardive dyskinesia), endocrine regulation (for example prolactin is too much), vasospasm (particularly in the brain vascular system), gastrointestinal tract disease (wherein relating to motility and secretory variation) and chronic paroxysmal hemicrania and the headache relevant with vascular disease).
Active compound of the present invention can be done antimigraine evaluation (P.P.A.Humphrey etc., Br.J.Pharmacol., 94,1128 (1988)) in the degree of shrinking by dog imitation sumatriptan in the isolating saphena bar by testing it.This effect can be by methiotepin, and a kind of known 5-hydroxytryptamine antagonist is blocked.Known sumatriptan can be used for treating migraine, and carotid artery vascular patience selectivity is increased.The pharmacological basis that sumatriptan is renderd a service is at people's such as W.Fenwick Br.J.Pharmacol., discusses in 96,83 (1989).
Serotonin 5-HT 1Agonist activity is as to 5-HT 1AThe described use of acceptor rat cortex be subjected to body source and ( 3H)-8-OH-DPAT makes radioligand people Eur.J.Pharm. such as (, 118,13 (1985)) D.Hoyer and as to 5-HT 1DThe described use oxtail of acceptor be subjected to body source and ( 3H) serotonin is made radioligand (R.E.Heuring and S.J.Peroutka, J.Neuroscience, 7,894 (1987)) and is measured in conjunction with testing by extracorporeal receptor.In the active compound of being tested, all IC that all demonstrate 50Be 250nM or lower.
Active combination is made the active and relevant pharmacological properties of antidepressive and can be measured by following method (1)-(4), these methods are described in Koe, B. wait people's Journal of Pharmacology andExperimental Therapeutics, 226 (3), 686-700 (1983).Specifically, activity can come be determined by following ability is studied: they influences the ability (Porsolt mouse " behavior disappointment " test) that mouse is fled from the effort of the case of swimming (1), and they strengthen the ability of the behavior symptom that the 5-hydroxytryptophan in the mouse brings out in vivo (2); (3) they in vivo the serotonin of antagonism parachloroamphetamine hydrochloride in rat brain reduce active ability and (4) they at the extracorporeal blocking serotonin, the ability that norepinephrine and Dopamine HCL are absorbed by the synaptosome rat cerebral cell.The cryogenic ability of serpentine that mouse is resisted in active combination in vivo is according to U.S. Patent No. 4,029, and method described in 731 is measured.
The present composition can use one or more pharmaceutically acceptable carriers to prepare in a usual manner.Therefore, active compound of the present invention can be prepared and be used for per os, through cheek, and in the nose, parenteral (for example intravenously, intramuscular or subcutaneous) or per rectum administration, or be mixed with and be suitable for through sucking or be blown into the form of administration.
For oral administration, pharmaceutical composition can be taked for example tablet or capsular form, they use the preparation of pharmaceutically acceptable vehicle by ordinary method, and these vehicle for example are tackiness agent (for example the W-Gum of pre-gelledization, polyvinylpyrrolidone or Vltra tears); Filler (for example lactose, Microcrystalline Cellulose or calcium phosphate); Lubricant (for example Magnesium Stearate, talcum or silica); Disintegrating agent (for example potato starch or sodium starch glycol); Or wetting agent (for example Sodium Lauryl Sulphate BP/USP).Tablet can coat with method well known in the art.Be used for peroral administration liquid preparation and can take for example solution, syrup or form of suspension, or they can be made into the dryness product, water or other suitable carriers preparation before use.This type of liquid preparation can be by ordinary method with acceptable additive preparation on the medicine, and these additives for example are suspension agent (for example Sorbitol Powder syrup, methylcellulose gum or hydrogenation edible fat); Emulsifying agent (for example Yelkin TTS or gum arabic); Nonaqueous carrier (for example Prunus amygdalus oil contains grease or ethanol); And sanitas (for example methyl p-hydroxybenzoate or propyl ester or Sorbic Acid (Sorbidacid)).
For through the cheek administration, said composition can be taked tablet or the lozenge form prepared in a usual manner.
Active compound of the present invention can be prepared and be used for through the injection administered parenterally, comprises and uses conventional catheter technique or infusion.Injection preparation can be unit dose shape, and for example ampoule or multi-dose container wherein are added with sanitas.Said composition can be taked such as suspension, the form of solution or the emulsion in oily or aqueous carrier, and can contain preparaton as suspending stable and/or dispersion agent.In addition, activeconstituents can be powder type, is used for preparing again with suitable carrier such as aseptic apirogen water before use.
Active compound of the present invention also can be made into per-rectum composition such as suppository or enema,retention, for example contains conventional suppository base such as theobroma oil or other glyceryl ester.
To going into intranasal administration or inhalation, active compound of the present invention can be easily with solution or form of suspension from being pushed by the patient or the pump spray containers of pumping is carried, or carry from pressurizing vessel or atomizer with aerosol spray form, use suitable volatilizer, Refrigerant 12 for example, Trichloromonofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas.Under the pressurised aerosol situation, dose unit can discharge to determine with metering by a valve is provided.Pressurizing vessel or atomizer can contain the solution or the suspension of active compound.Being used for the capsule of sucker or insufflator and cartridge case (for example by the gelatin manufacturing) can be mixed with and contain The compounds of this invention and the suitable powder matrix such as the powdered mixture of lactose or starch.
The per os that is used for the treatment of above mentioned disease (for example migraine), parenteral or the recommended doses that delivers medicine to the active compound of the present invention of normal adult through cheek are 0.1-200mg activeconstituents/unitary dose, but administration every day 1-4 time.
The dosage or " one " that are used for preferably making at the aerosol formulation of normal adult treatment disease above-mentioned (for example migraine) each metering of aerosol contain 20 μ g-1000 μ g The compounds of this invention.Total per daily dose of aerosol is 100 μ g-10mg.Administration in one day several times, and is for example, 2,3,4 or 8 times, each 1,2, or 3 dosage.
About active compound of the present invention and 5-HT reuptake inhibitor, preferred Sertraline is used for the treatment of the main body with above-mentioned arbitrary symptom together, should note these compounds can be by aforementioned arbitrary approach individually dosed or with pharmaceutically acceptable carrier combinations administration, and this administration can single dose or multiple doses carry out.More particularly, active combination can many different agent shape administrations, promptly they can with various pharmaceutically acceptable inert supports with tablet, capsule, lozenge, lozenge, hand shape sugar (handcandy), pulvis, sprays, aqeous suspension, Injectable solution, elixir, the combination of forms such as syrup.Examples of such carriers comprises solid diluent or filler, sterile aqueous media and various nonpoisonous organic solvents etc.In addition, this type of oral pharmaceutical formulations is sweetening and/or seasoning suitably, carries out with various types of reagent that are usually used in these purposes.Usually, formula I compound is present in these agent shapes with the concentration level of the about 90wt% total composition of about 0.5wt%-, promptly present in an amount at least sufficient to the unitary dose that provides required, and the 5-HT reuptake inhibitor, preferred Sertraline is present in these agent shapes with the concentration level of the about 90wt% total composition of about 0.5wt%-, promptly presents in an amount at least sufficient to the unitary dose that provides required.Compound of the present invention can be different the polymorph form have promptly different crystallized forms.
Active compound of the present invention is being used for the treatment of the per os of disease above-mentioned, parenteral, the suggestion per daily dose that rectum or cheek deliver medicine in the combination preparation (preparation that contains active compound of the present invention and 5-HT reuptake inhibitor) of normal adult is the about 2000mg of about 0.01mg-, the preferred about 200mg formula of about 0.1mg-I activeconstituents/unitary dose can administration in a day 1-4 time.
The 5-HT reuptake inhibitor, preferred Sertraline, be used for the treatment of the per os of disease above-mentioned, the suggestion per daily dose that parenteral or cheek deliver medicine in the combination preparation of normal adult is the about 2000mg of about 0.1mg-, the preferred about 200mg5-HT reuptake inhibitor/unitary dose of about 1mg-can administration in a day 1-4 time.
Sertraline and active compound of the present invention are being used for the treatment of the per os of disease above-mentioned, and parenteral or cheek deliver medicine to preferred dose in the combination preparation of normal adult than for about 0.00005-is about 20000, preferably about 0.25-about 2000.
The dosage or " one " that are used for preferably making at the aerosol combination preparation of normal adult treatment disease above-mentioned each metering of aerosol contain the about 1000 μ g of the 0.01 μ g-that has an appointment active compound of the present invention, preferred this compound of the about 10mg of about 1 μ g-.Can administration in a day several times, for example 2,3,4 or 8 times, for example give 1,2 or 3 dosage at every turn.
The dosage or " one " that are used for preferably making at the aerosol formulation of normal adult treatment disease above-mentioned each metering of aerosol contain the about 2000mg5-HT reuptake inhibitor of the 0.01mg-that has an appointment, preferred Sertraline, preferably about 1mg-200mg Sertraline.Can administration in a day several times, for example 2,3,4 or 8 times, for example give 1,2 or 3 dosage at every turn.
As previously mentioned, with the 5-HT reuptake inhibitor of formula I compound combination, preferred Sertraline is very suitable for as thymoleptic.Usually, these contain the 5-HT reuptake inhibitor, the antidepressant composition of preferred Sertraline and formula I compound is usually with the about 100mg5-HT reuptake inhibitor of about 0.01mg-, the preferred dosed administration of Sertraline/kg body weight/day, the about 10mg Sertraline of preferably about 0.1mg-/kg body weight/day; The about 100mg formula of about 0.001mg-I compound/kg body weight/day, the about 10mg formula of preferably about 0.01mg-I compound/kg body weight/day, but according to being changed by the situation of treatment main body and selected concrete route of administration.
The preparation of the following example explanation The compounds of this invention.Fusing point is not calibrated.The NMR data write down also reference from sample solvent (deuterochloroform, deuterium lock signal unless otherwise) with per 1,000,000 umber (δ).Specific rotation uses sodium D-line (589nm) at room temperature to measure.Be purchased reagent and need not to be further purified direct use.THF refers to tetrahydrofuran (THF).DMF refers to N, dinethylformamide.Chromatography refers to the column chromatography using 32-63 μ m silica gel and carry out under nitrogen pressure (flash chromatography) condition.Room temperature refers to 20-25 ℃.All non-aqueous reactions carry out under nitrogen atmosphere for simplicity and for making productive rate reach maximum.Concentrating under reduced pressure refers to use Rotary Evaporators.
Embodiment 1
1-methyl-4-(7-(5-phenyl-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl) piperazine dihydrochloride dihydrate
At the anhydrous N of 2.0ml, add 1-(7-hydroxyl the naphthyl)-4-methylpiperazine of 400mg (1.65mmol) in 4.0mlDMF toward the no oily sodium hydride of 80mg (3.33mmol) in the solution of dinethylformamide (DMF).After the stirring at room 20 minutes, add 380mg (1.95mmol) reactant 5-chloromethyl-3-phenyl-1,2, the 4-oxadiazole in 2.0mlDMF solution and with mixture 90 ℃ of heating 16 hours.Then reaction solution is chilled to the about 50mlH of room temperature and impouring 2Among the O.Stir after 20 minutes, product is extracted in the ether, use H 2MgSO is used in the O washing 4Dry and evaporate reddish oil.Use methyl alcohol/dense ammonium hydroxide/methylene dichloride (CH 3OH: dense NH 4OH: CH 2Cl 2) (2.5: 0.5: 97) separate in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, obtains the pure free alkali of faint yellow oily.This oil is dissolved in the ethyl acetate and handles, place that title product precipitates 311mg (47%), Mp82 ℃ after about 30 minutes with colorless solid with the saturated ethyl acetate of hydrogen chloride gas (HCl). 1H-NMR (CDCl 3, free alkali) δ 2.5 (s, 3H), 2.7 (bs, 4H), 3.1 (bs, 4H), 5.2 (s, 2H), 6.5 (d, 1H), 7.1 (dd, 1H), 7.2-7.6 (m, 9H), 7.7 (d, 1H).Mass spectrum (m/e, %), 401 (M + 1, 100), 373 (5), 272,255,243.C 24H 24N 4O 22HCl2H 2The ultimate analysis calculated value of O: C, 56.58; H, 5.94; N, 11.00.Measured value: C, 56.36; H, 6.21; N, 10.87.
By the method identical, but the reactant difference, prepare the following compound of embodiment 2-40 similarly with embodiment 1:
Embodiment 2
1-methyl-4-(7-(1-phenyl-1H-tetrazolium-5-base oxygen base) naphthalene-1-yl) piperazine dihydrochloride
219 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ?2．4(s，3H)，2．7(bs，4H)，3．2(bs，4H)，7．2(d，1H)，7．4(m，2H)，7．6(m，4H)，7．9(m，3H)，8．3(d，1H)。
Mass spectrum: m/e387 (M + 1).
C 22H 22N 6The ultimate analysis calculated value of O2HCl: C, 57.52; H, 5.27; N, 18.29.
Measured value: C, 57.78; H, 5.72; N, 18.40.
Embodiment 3
1-methyl-4-{7-(5-(3-trifluoromethyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl } piperazine dihydrochloride
175 ℃ of MP (decomposition)
1H?NMR(CDCl 3)δ2．4(s，3H)，2．8(bs，4H)，3．2(bs，4H)，5．5(s，2H)，7．1(d，1H)，7．3(m，2H)，7．5(d，1H)，7．7(t，2H)，7．8(d，1H)，7．9(d，1H)，8．3(d，1H)，8．5(d，1H)。
Mass spectrum: m/e387 (M + 1).
C 25H 23F 3N 4O 22HClH 2The ultimate analysis calculated value of O: C, 53,67; H, 4.87; N, 10.02.
Measured value: C, 53.64; H, 5.27; N, 9.86.
Embodiment 4
1-{7-(5-(3-methoxyphenyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate
174 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．5(s，3H)，2．7(bs，4H)，3．2(bs，4H)，4．0(s，3H)，5．5(s，2H)，7．1(m，2H)，7．3(m，2H)，7．5(m，2H)，7．7(m，2H)，7．9(d，2H)。
Mass spectrum: m/e432 (M + 2).
C 25H 26N 4O 32HClH 2The ultimate analysis calculated value of O: C, 57.58; H, 5.80; N, 10.75.
Measured value: C, 58.03; H, 6.20; N, 10.78.
Embodiment 5
1-{7-(5-(3,5-dimethyl isoxazole-4-yl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate
Mp?222-223℃。
1H?NMR(CDCl 3)δ2．5(s，3H)，2．6(s，3H)，2．7(bs，4H)，2．8(s，3H)，3．2(bs，4H)。5．5(s，2H)，7．1(d，1H)，7．4(m，2H)，7．5(d，1H)，7．7(d，1H)，7．8(d，1H)。
Mass spectrum: m/e420 (M + 1).
C 23H 25N 5O 32HClH 2The ultimate analysis calculated value of O: C, 54.12; H, 5.73; N, 13.72.
Measured value: C, 53.75; H, 6.02; N, 13.66.
Embodiment 6
1-{7-(5-(2-methoxyphenyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate
186 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．5(s，3H)，2．7(bs，4H)，3．2(bs，4H)，4．0(s，3H)，5．5(s，2H)，7．1(m，3H)，7．3(m，2H)，7．5(m，2H)，7．7(d，1H)，7．8(d，1H)，8．1(bs，1H)。
Mass spectrum: m/e432 (M + 2).
C 25H 26N 4O 32HClH 2The ultimate analysis calculated value of O: C, 57.58; H, 5.80; N, 10.75.
Measured value: C, 57.67; H, 5.95; N, 10.72.
Embodiment 7
1-(7-(the 5-tertiary butyl-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine hydrochloride dihydrate
85 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ1．5(s，9H)，2．5(s，3H)，2．8(bs，4H)，3．2(bs，4H)，5．4(s，2H)，7．1(d，1H)，7．3(m，2H)，7．5(d，1H)，7．7(d，1H)，7．8(d，1H)。
Mass spectrum: m/e381 (M + 1).
C 22H 28N 4O 2HCl2H 2The ultimate analysis calculated value of O: C, 58.33; H, 7.34; N, 12,37.
Measured value: C, 58.52; H, 7.18; N, 12.39.
Embodiment 8
1-methyl-4-(7-(3-phenyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl) piperazine dihydrochloride semihydrate
160 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．4(s，3H)，2．7(bs，4H)，3．2(bs，4H)，5．6(s，2H)，7．1(d，1H)，7．3(m，2H)，7．5(m，4H)，7．6(d，1H)，7．8(d，1H)，8．2(m，2H)。
Mass spectrum: m/e401 (M + 1).
C 24H 24N 4O 22HCl0.5H 2The ultimate analysis calculated value of O: C, 59.75; H, 5.64; N, 11.61.
Measured value: C, 59.50; H, 5.70; N, 11.47.
Embodiment 9
1-7-(5-(4-methoxyphenyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate
149 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．5(s，3H)，2．7(bs，4H)，3．2(bs，4H)，3．9(s，3H)，5．4(s，2H)，7．0(d，2H)，7．1(d，1H)，7．25(m，2H)，7．5(d，1H)，7．65(d，1H)，7．7(d，1H)，8．1(d，2H)。
Mass spectrum: m/e431 (M + 1).
C 25H 26N 4O 32HCl1.5H 2The ultimate analysis calculated value of O: C, 56.60; H, 5.89; N, 10.56.
Measured value: C, 56.30; H, 5.76; N, 10.28.
Embodiment 10
1-{7-(5-(4-chloro-phenyl-)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride dihydrate
186 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．5(s，3H)，2．7(bs，4H)，3．2(bs，4H)，5．4(s，2H)，7．05(d，1H)，7．25(m，2H)，7．5(d，3H)，7．65(d，1H)，7．7(d，2H)，8．1(d，2H)。
Mass spectrum: m/e435 (M + 1).
C 24H 23N 4O 22HCl2H 2The ultimate analysis calculated value of O: C, 53.00; H, 5.37; N, 10.30.
Measured value: C, 52.95; H, 5.05; N, 10.22.
Embodiment 11
1-{7-(5-(2, the 4-dichloro benzyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate
90 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．5(s，3H)，2．7(bs，4H)，3．1(bs，4H)，5．3(s，2H)，5．4(s，2H)，6．8(m，1H)，7．1(m，2H)，7．3(m，2H)，7．4(d，1H)，7．5(d，1H)，7．6(d，1H)，7．7(d，1H)。
Mass spectrum: m/e499 (M + NH3).
C 25H 24N 4O 3Cl 22HClH 2The ultimate analysis calculated value of O: C, 50.86; H, 4.78; N, 9.49.
Measured value: C, 51.24; H, 4.70; N, 9.38.
Embodiment 12
1-{7-(3-(4-benzyl chloride base)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride semihydrate
118 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．5(s，3H)，2．7(bs，4H)，3．1(bs，4H)，4．1(s，2H)，5．4(s，2H)，7．1(d，1H)，7．15-7．4(m，6H)，7．5(d，1H)，7．6(d，1H)，7．7(d，1H)。
Mass spectrum: m/e449 (M + 1).
C 25H 25ClN 4O 22HCl0.5H 2The ultimate analysis calculated value of O: C, 56.56; H, 5.32; N, 10.55.
Measured value: C, 56.89; H, 5.24; N, 10.56.
Embodiment 13
5-chloro-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) benzoxazole dihydrochloride
195 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．5(s，3H)，2．7(bs，4H)，3．1(bs，4H)，5．5(s，2H)，7．1(d，1H)，7．2-7．4(m，3H)，7．5(m，2H)，7．6-7．8(m，3H)。
Mass spectrum: m/e408 (M + 1).
C 23H 22ClN 3O 2The ultimate analysis calculated value of 2HCl: C, 57.45; H, 5.03; N, 8.74.
Measured value: C, 57.11, H, 5.10; N, 8.69.
Embodiment 14
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl)-5-trifluoromethyl benzo thiazole dihydrochloride dihydrate
179 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．5(s，3H)，2．6(bs，4H)，3．1(bs，4H)，5．2(s，2H)，7．0(d，1H)，7．2(m，2H)，7．5(d，1H)，7．6(m，2H)，7．7(d，1H)，8．0(d，1H)，8．3(s，1H)。
Mass spectrum: m/e458 (M + 1).
C 24H 22F 3N 3OS2HCl2H 2The ultimate analysis calculated value of O: C, 46.10; H, 4.64; N, 6.45.
Measured value: C, 46.56; H, 4.70; N, 6.55.
Embodiment 15
1-{7-(3-(4-methoxyphenyl)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride semihydrate
184 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．4(s，3H)，2．7(bs，4H)，3．1(bs，4H)，3．8(s，3H)，5．5(s，2H)，7．0(d，2H)，7．1(d，1H)，7．2(m，2H)，7．5(d，1H)，7．6(d，1H)，7．7(d，1H)，8．0(d，2H)。
Mass spectrum: m/e431 (M + 1).
C 25H 26N 4O 32HCl0.5H 2The ultimate analysis calculated value of O: C, 58.59; H, 5.70; N, 10.93.
Measured value: C, 56.68; H, 5.43; N, 10.72.
Embodiment 16
1-{7-(3-(2-methoxyphenyl)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate
206 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．4(s，3H)，2．7(bs，4H)，3．1(bs，4H)，3．9(s，3H)，5．5(s，2H)，7．0(m，3H)，7．2(m，2H)，7．4(m，2H)，7．6(d，1H)，7．7(d，1H)，8．2(dd，1H)。
Mass spectrum: m/e431 (M + 1).
C 25H 26N 4O 32HClH 2The ultimate analysis calculated value of O: C, 57.58; H, 5.80; N, 10.75.
Measured value: C, 57.70; H, 5.48; N, 10.37.
Embodiment 17
1-7-(3-(4-chloro-phenyl-)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride
Mp 231-232 ℃ (decomposition)
1H?NMR(CDCl 3)δ2．4(s，3H)，2．7(bs，4H)，3．2(bs，4H)，5．5(s，2H)，7．1(d，1H)，7．3(m，2H)，7．5(m，3H)，7．6(d，1H)，7．7(d，1H)，8．0(d，2H)。
Mass spectrum: m/e435 (M + 1).
C 24H 23ClN 4O 2The ultimate analysis calculated value of 2HCl: C, 56.76; H, 4.96; N, 11.03.
Measured value: C, 56.36; H, 4.88; N, 10.78.
Embodiment 18
1-7-(5-(2-methoxyphenyl)-(1,2,4 〕 oxadiazoles-3-ylmethoxy methyl) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate
135 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．5(s，3H)，2．7(bs，4H)，3．2(bs，4H)，4．0(s，3H)，4．9(s，2H)，5．0(s，2H)，7．1(m，3H)，7．4(t，1H)，7．5(m，3H)，8．1(dd，1H)，8．2(s，1H)。
Mass spectrum: m/e444 (M + 1)
C 26H 28N 4O 32HCl1.5H 2The ultimate analysis calculated value of O: C, 57.35; H, 6.11; N, 10.29.
Measured value: C, 57.31; H, 6.20; N, 10.20.
Embodiment 19
1-(7-{1-(5-(4-chloro-phenyl-)-(1,3,4 〕 oxadiazole-2-yl) oxyethyl group } naphthalene-1-yl }-4-methylpiperazine hydrochloride dihydrate
65 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．0(d，3H)，2．5(s，3H)，2．7(bs，4H)，3．2(m，4H)，5．9(q，1H)，7．1(d，1H)，7．2-7．4(m，2H)，7．5(m，3H)，7．7(d，1H)，7．75(d，1H)，8．0(d，2H)。
Mass spectrum: m/e449 (M + 1)
C 25H 25ClN 4O 2HCl2H 2The ultimate analysis calculated value of O: C, 57.58; H, 5.80; N, 10.74.
Measured value: C, 58.15; H, 5.99; N, 10.52.
Embodiment 20
1-{7-(3-(2-fluorophenyl)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride
Mp?144℃。
1H?NMR(CDCl 3)δ2．4(s，3H)，2．74(bs，4H)，3．09(bs，4H)，5．54(s，2H)，7．12(dd，1H)，7．21-7．35(m，4H)，7．51(m，2H)，7．60(d，1H)，7．79(d，1H)，8．08(t，1H)。
Mass spectrum: m/e419 (M + 1)
C 24H 23FN 4O 22HCl1H 2The ultimate analysis calculated value of O: C, 56.58; H, 5.34; N, 11.00.
Measured value: C, 56.71; H, 5.40; N, 10.86.
Embodiment 21
5-bromo-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) benzoxazole dihydrochloride
182 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．44(s，3H)，2．67(bs，4H)，3．07(bs，4H)，5．48(s，2H)，7．11(dd，1H)，7．29(m，2H)，7．41-7．52(m，3H)，7．66(d，1H)，7．77(d，1H)，7．89(d，1H)。
Mass spectrum: m/e452 (M + 1)
C 23H 22BrN 3O 22HC10.5H 2The ultimate analysis calculated value of O: C, 51.70; H, 4.72; N, 7.86.
Measured value: C, 52.07; H, 4.62; N, 7.74.
Embodiment 22
6-fluoro-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) benzoxazole dihydrochloride
175 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．44(s，3H)，2．70(bs，4H)，3．08(bs，4H)，5．47(s，2H)，7．12(m，2H)，7．25-7．33(m，3H)，7．51(d，1H)，7．68(m，2H)，7．78(d，1H)。
Mass spectrum: m/e392 (M + 1).
Embodiment 23
6-methoxyl group-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) benzothiazole dihydrochloride
191 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．42(s，3H)，2．63(bs，4H)，3．03(bs，4H)，3．87(s，3H)，5．61(s，2H)，7．10(m，2H)，7．25-7．33(m，3H)，7．50(d，1H)，7．63(d，1H)，7．78(d，1H)，7．93(d，1H)。
Mass spectrum: m/e420 (M + 1)
C 24H 25N 3O 2S3HCl3H 2The ultimate analysis calculated value of O: C, 49.45; H, 5.88; N, 7.21.
Measured value: C, 49.75; H, 5.83; N, 7.02.
Embodiment 24
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base) pyrimidine
Mp 150-152 ℃ (decomposition)
1H?NMR(CDCl 3)δ2．33(s，3H)，2．61(bs，4H)，3．08(bs，4H)，6．95(t，1H)，7．06(d，1H)，7．30(m，2H)，7．50(d，1H)，7．82(d，1H)，8．00(s，1H)，8．48(d，2H)。
C 19H 20N 4The HRMS calculated value of O: 320.1642.
Measured value: 320.16536.
Embodiment 25
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base)-5-trifluoromethyl pyrimidine
Mp 84-86 ℃ (decomposition)
1H?NMR(CDCl 3)δ2．37(s，3H)，2．65(bs，4H)，3．12(bs，4H)，7．03(d，1H)，7．13(d，1H)，7．25(dd，1H)，7．40(t，1H)，7．56(d，1H)，7．88(d，1H)，7．95(d，1H)，8．45(d，1H)。
Mass spectrum: m/e388 (M + 1)
Embodiment 26
5-fluoro-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base) pyrimidine
1H?NMR(CDCl 3)δ2．45(s，3H)，2．70(bs，4H)，3．15(bs，4H)，7．12(d，1H)，7．20(dd，1H)，7．30(dd，1H)，7．40(t，1H)，7．55(t，1H)，7．80-7．95(m，2H)，8．00(d，1H)，8．45(s，1H)。
Embodiment 27
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) quinoline
1H?NMR(CDCl 3)δ2．3(s，3H)，2．6(bs，4H)，3．2(bs，4H)，7．1(m，2H)，7．4(m，3H)，7．6(m，2H)，7．7(m，2H)，7．8(d，1H)，8．1(d，1H)，8．2(d，1H)。
Mass spectrum: m/e370 (M + 1)
C 24H 23N 3The HRMS calculated value of O: 369.1841.
Measured value: 369.18087.
Embodiment 28
1-(7-(5-chloropyridine-2-base oxygen base) naphthalene-1-yl)-4-methylpiperazine
1H?NMR(CDCl 3)δ2．38(s，3H)，2．65(bs，4H)，3．12(bs，4H)，6．90(d，1H)，7．11(d，1H)，?7．23(dd，1H)，7．37(t，1H)，7．55(d，1H)，7．65(dd，1H)，7．84(d，1H)，7．90(d，1H)，8．12(d，1H)。
C 20H 20ClN 3The HRMS calculated value of O: 353.1295.
Measured value: 353.11642.
Embodiment 29
1-(7-(5-chlorothiophene-2-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine
mp83-85℃
Mass spectrum: m/e373 (M + 1)
1H?NMR(CDCl 3)δ2．43(s，3H)，2．70(bs，4H)，3．10(bs，4H)，5．25(s，2H)，6．80(d，1H)，6，90(d，1H)，7．10(d，1H)，7．16(dd，1H)，7．27(t，1H)，7．50(d，1H)，7．58(d，1H)，7．75(d，1H)。
Embodiment 30
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base) cigarette nitrile (nicotinonitrile)
1H?NMR(CDCl 3)δ2．37(s，3H)，2．65(bs，4H)，3．10(bs，4H)，7．05(dd，1H)，7．10(d，1H)，7．25(dd，1H)，7．37(t，1H)，7．55(d，1H)，7．85(d，1H)，7．98(dd，2H)，8．25(dd，1H)。
C 21H 20N 4The HRMS calculated value of O: 344.1637.
Measured value: 344.16176.
Embodiment 31
2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) quinoline
1H?NMR(CDCl 3)δ2．25(s，3H)，2．35(bs，4H)，2．85(bs，4H)，5．55(s，2H)，7．0(d，1H)，7．2(t，1H)，7．3(dd，1H)，7．45(m，3H)，7．6(d，1H)，7．7(m，3H)，8．05(d，1H)，8．15(d，1H)。
C 25H 25N 3The HRMS calculated value of O: 383.1992
Measured value: 383.19964
Embodiment 32
2-(8-(1-methyl piperidine-4-yl) naphthalene-2-base oxygen base) pyrimidine
Mp?134-135℃。
1H?NMR(CDCl 3)δ2．01(m，4H)，2．25(m，2H)，2．41(s，3H)，3．11(bd，2H)，3．21(m，1H)，7．07(t，1H)，7．35(dd，1H)，7．44(d，1H)，7．45(s，1H)，7．74(m，1H)，7．89(d，1H)，7．93(d，1H)，8．59(d，2H)。
C 20H 21N 3The HRMS calculated value of O: 319.1680
Actual measurement m/e:319.1676
C 20H 21N 3OH 2The ultimate analysis calculated value of O: C, 73.15; H, 6.75; N, 12.79.
Measured value: C, 72.94; H, 6.78; N, 12.66.
Embodiment 33
1-methyl-4-(7-(3-phenyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl) piperidines
Mp?106-108℃。
1H?NMR(CDCl 3)δ1．85-2．03(m，4H)，2．22(m，2H)，2．36(s，3H)，3．02(bd，2H)，3．13(m，1H)，5．50(s，2H)，7．25-7．42(m，3H)，7．45-7．58(m，4H)，7．65(d，1H)，7．82(d，1H)，8．10(dd，2H)。
C 25H 25N 3O 2The HRMS calculated value: 399.4914
Actual measurement m/e:399.1965
C 25H 25N 3O 20.25H 2The ultimate analysis calculated value of O: C, 74.33; H, 6.36; N, 10.40
Measured value: C, 74.23; H, 6.42; N, 10.49.
Embodiment 34
1-methyl-4-(7-(pyridine-2-ylmethoxy) naphthalene-1-yl) piperazine
1H?NMR(CDCl 3)δ2．38(s，3H)，2．60(bs，4H)，?2．99(bs，4H)，5．35(s，2H)，7．03(d，1H)，7．23(m，3H)，7．43-7．53(m，3H)，7．63(m，1H)，7．71(d，1H)，8．59(m，1H)。
C 21H 23N 3The HRMS calculated value of O: 333.1841
Actual measurement m/e:333.18425
Embodiment 35
1-methyl-4-(7-(3-pyridin-3-yl propoxy-) naphthalene-1-yl) piperazine
1H?NMR(CDCl 3)δ2．2(q，2H)，2．4(s，3H)，2．75(bs，4H)，2．9(t，2H)，3．15(bs，4H)，4．1(t，2H)，7．05-7．30(m，4H)，7．5(m，3H)，7．7(d，1H)，8．45(dd，1H)，8．52(d，1H)。
C 23H 27N 3The HRMS calculated value of O: 361.2148
Actual measurement m/e:361.21118
Embodiment 36
1-{7-(2-(4-chloro-phenyl-) thiazole-4-ylmethoxy) naphthalene-1-yl }-the 4-methylpiperazine
1H?NMR(CDCl 3)δ2．25(s，3H)，2．6(bs，4H)，3．05(bs，4H)，5．4(s，2H)，7．05(d，1H)，7．25(m，3H)，7．35(m，2H)，7．5(d，1H)，7．55(d，1H)，7．75(d，1H)，7．85(d，2H)。
C 25H 24ClN 3The HRMS calculated value of OS: 449.1407
Actual measurement m/e:449.13387
Embodiment 37
4-{7-(5-(3,5-dimethyl isoxazole-4-yl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-the 1-methyl piperidine
Mp?84-86℃。
1H?NMR(CDCl 3)δ1．80-2．00(m，4H)，2．23(dt，2H)，2．39(s，3H)，2．59(s，3H)，2．81(s，3H)，3．06(bd，2H)，3．18(m，1H)，5．40(s，2H)，7．26-7．32(m，1H)，7．36(d，1H)，7．41(dd，1H)，7．56(d，1H)，7．67(d，1H)，7．82(d，1H)。
C 24H 26N 4O 3The HRMS calculated value: 418.1999
Actual measurement m/e:418.1996
Embodiment 38
7-chloro-2-(8-(4-methylpiperazine-1-yl) naphthalene-2-yloxymethyl) quinoline
Mp 246-247 ℃ (decomposition)
1H?NMR(CDCl 3)δ2．30(s，3H)，2．40(bs，4H)，2．86(bs，4H)，5．52(s，2H)，7．01(d，1H)，7．25(m，2H)，7．45(m，3H)，7．63(m，2H)，7．73(d，1H)，8．02(d，1H)，8．13(d，1H)。
13H?NMR(CDCl 3)ppm：46．1，52．2，55．5，71．1，103．9，115．4，118．7，119．1，123．2，123．9，125．8，127．5，128．2，128．9，129．8，130．2，130．3，135．6，136．6，148．0，148．6，155．9，159．7。
Mass spectrum: m/e418 (M + 1)
Embodiment 39
6-chloro-5-{2-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base) ethyl }-1, the 3-Indolin-2-one
93 ℃ of Mp (decomposition)
1H?NMR(CDCl 3)δ2．4(s，3H)，2．75(bs，4H)，3．15(bs，4H)，3．25(t，2H)，3．50(s，2H)，4．35(t，2H)，6．9(s，1H)，7．1(t，2H)，7．25(t，2H)，7．50(d，1H)，7．55(m，1H)，7．70(d，1H)，9．40(s，1H)。
C 25H 26ClN 3O 2The HRMS calculated value: 435.1714
Measured value: 435.17042
Embodiment 40
3-(8-(4-methylpiperazine-1-yl) naphthalene-2-base oxygen base)-6-phenyl pyridazine
Mp?158-160℃。
1H?NMR(CDCl 3)δ2．35(s，3H)，2．64(bs，4H)，3．12(bs，4H)，7．11(d，1H)，7．23(t，1H)，7．33-7．46(m，5H)，7．55(d，1H)，7．85(m，2H)，8．00(m，3H)。
Mass spectrum: m/e397 (M + 1)
The compound for preparing the following example according to the method for existing resigned U.S. Patent application 08/032,042 and PCT application number PCT/US94/01206.
Embodiment 41
8-(4-methylpiperazine-1-yl) naphthalene-2-carboxylic acid (1-(4-chloro-phenyl-) ethyl) acid amides
Mp?152．5-153℃。
1H?NMR(CDCl 3)δ1．65(d，3H)，2．45(s，3H)，2．75(bs，4H)，3．20(bs，4H)，5．38(m，1H)，6．45(d，1H)，7．15(dd，1H)，7．27?(s，1H)，7．40(m，3H)，7．50(t，1H)，7．60(d，1H)，7．75(dd，1H)，7．90(d，1H)，8．75(s，1H)。
Mass spectrum: m/e407 (M +)
Embodiment 42
8-(4-methylpiperazine-1-yl) naphthalene-2-carboxylic acid (3-(4-chloro-phenyl-) propyl group) acid amides
Mp?121．5-123℃。
1H?NMR(CDCl 3)δ2．05(m，2H)，2．45(s，2H)，2．75(m，6H)，3．20(bs，4H)，3．55(m，2H)，6．35(bs，1H)，7．10-7．35(m，5H)，7．48(m，1H)，7．55(d，1H)，7．68(m，1H)，7．85?(dd，1H)，8．68(bs，1H)。
Mass spectrum: m/e421 (M +)
Embodiment 43
8-(piperazine-1-yl) naphthalene-2-carboxylic acid 4-chlorobenzamide
1H?NMR(CDCl 3)δ1．78(s，1H)，3．05(m，9H)，4．60(d，2H)，6．85(t，1H)，7．07(dd，1H)，7．23(m，3H)，7．45(m，2H)，7．74(m，2H)，8．65(s，1H)。
Embodiment 44
8-(4-methylpiperazine-1-yl) naphthalene-2-carboxylic acid (4-benzyl chloride base) methyl nitrosourea dihydrochloride
1H NMR (CDCl 3, free alkali) δ 2.7 (s, 1H), 2.95-3.80 (m, 13H), 4.07 (d, 1H), 4.7 (d, 1H), 7.2-7.65 (m, 7H), 7.75 (d, 1H), 7.95 (d, 1H), 8.25 (d, 1H).
Mass spectrum: m/e407 (M + 1)
Embodiment 45
8-(4-methylpiperazine-1-yl) naphthalene-2-carboxylic acid (2-(4-chloro-phenyl-) ethyl) acid amides
Mp?122-123℃。
1H?NMR(CDCl 3)δ2．45(s，3H)，2．77(bs，4H)，2．95(t，2H)，3．12(bs，4H)，3．32(m，1H)，3．68(t，2H)，7．17(dd，1H)，7．30(m，4H)，7．50(t，1H)，7．60(d，1H)，7．80(dd，1H)，7．90(d，1H)，8．62(d，1H)。
Mass spectrum: m/e408 (M + 1)
Embodiment 46
8-(4-methylpiperazine-1-yl) naphthalene-2-carboxylic acid pyrimidine-4-base acid amides
1H?NMR(CDCl 3)δ2．36(s，3H)，2．70(bs，4H)，3．10(bs，4H)，7．15(dd，1H)，7．55(q+t，2H)，7．91(d，1H)，8．41(dd，1H)，8．65(d，1H)，8．73(d，1H)，8．82(s，1H)，9．48(s，1H)。
C 20H 21N 5The HRMS calculated value of O: 347,1742
Measured value: 347.16974
The compound of embodiment 47-50 is by the intermediate preparation of preparation 5.
Embodiment 47
1-(1-methyl piperidine-4-yl)-7-naphthoic acid 3-phenyl propyl acid amides
Seal 1-(1-methyl piperidine-4-yl)-7-trifluoromethane sulfonyloxy naphthalene (0.25g with carbon monoxide atmosphere (gas cylinder), 0.67mmol), triethylamine (0.373ml, 2.68mmol), 3-phenylpropylamine (0.286ml, 2.01mmol) and chlorination two (triphenylphosphine) palladium (0.025g, mixture 0.033mmol) also is heated to 105 ℃, keeps 16 hours.With the ethyl acetate dilute reaction solution and use diatomite filtration.Filtrate water and salt water washing, dry and concentrated.Resistates carries out flash chromatography and separates (1 * 3 inch, with the filling of 75% ethyl acetate/hexane) on silica gel.Wash-out amine is following to carry out: 75% ethyl acetate/hexane, 150ml, zero; Ethyl acetate, 150ml, zero; 2% methyl alcohol/1% triethylamine/ethyl acetate, 200ml and 2% methyl alcohol/1% triethylamine/ethyl acetate, 100ml, 0.21g oily matter.Impurity (120 ℃ of jar Wen Gaoda, 1mm mercury (Hg)) is removed in ball-ball distillation.Resistates is a pure products in jar, heavy 0.190g (73%).The 1-that obtains in this way during placement (1-methyl piperidine-4-yl)-7-naphthoic acid 3-phenyl propyl acid amides solidifies, mp 47-50 ℃; 1H NMR (250MHz, CDCl 3) δ 8.67 (s, 1H), 7.86 (d, J=8.5Hz, 1H), 7.73 (d, J=6.5Hz, 1H), 7.61-7.43 (m, 3H), 7.36-7.18 (m, 5H), 6.33 (brs, 1H), 3.58 (q, J=6.5Hz, 2H), 3.42 (symm, 1H), 3.05 (brd, J=11.5Hz, 2H), 2.77 (t, J=7.5Hz, 2H), 2.38 (s, 3H), 2.27 (symm, 2H), 2.10-1.88 (m, 6H).C 26H 30N 2O0.75H 2The ultimate analysis calculated value of O: C, 78.06; H, 7.94; N, 7.00.Measured value: C, 77.92; H, 7.91; N, 6.70.
Embodiment 48
1-(1-methyl piperidine-4-yl)-7-naphthoic acid 3-(4-chloro-phenyl-) propyl amides
Seal 1-(1-methyl piperidine-4-yl)-7-trifluoromethane sulfonyloxy naphthalene (0.25g with carbon monoxide atmosphere (gas cylinder), 0.67mmol), triethylamine (0.373ml, 2.68mmol), 3-(4-chloro-phenyl-) propylamine (0.341ml, 2.01mmol) and chlorination two (triphenylphosphine) palladium (0.025g, mixture 0.033mmol) also is heated to 105 ℃, keeps 16 hours.With the ethyl acetate dilute reaction solution and use diatomite filtration.Filtrate water and salt water washing, dry and concentrated.Resistates carries out flash chromatography and separates (1 * 3 inch, with the filling of 75% ethyl acetate/hexane) on silica gel.Wash-out amine is following to carry out: 75% ethyl acetate/hexane, 150ml, zero; Ethyl acetate, 150ml, zero; 2% methyl alcohol/1% triethylamine/ethyl acetate, 200ml and 2% methyl alcohol/1% triethylamine/ethyl acetate, 150ml, the slow crystalline yellow oil of 0.196g.This material obtains the white crystalline 1-of 0.064g (23%) (1-methyl piperidine-4-yl)-7-naphthoic acid 3-(4-chloro-phenyl-) propyl amides, mp132-133.5 ℃ with chloroform/ether recrystallization; 1HNMR (250MHz, CDCl 3) δ 8.66 (s, 1H), 7.87 (d, J=8.5Hz, 1H), 7.72 (d, J=7.5Hz, 1H), 7.58-7.46 (m, 3H), 7.27-7.23 (m, 2H, partly fuzzy by the NMR solvent), 7.15 (d of long-range coupling, J=8.5Hz, 2H), 6.23 (brt, 1H), 3.55 (q, J=6.5Hz, 2H), 3.39 (symm, 1H), 3.02 (brd, J=12Hz, 2H), 2.72 (t, J=7.5Hz, 2H), 2.36 (s, 3H), 2.23 (symm, 2H), 2.04-1.89 (m, 6H).
C 26H 29ClN 2O0.25H 2The ultimate analysis calculated value of O: C, 73.40; H, 6.99; N, 6.58.
Measured value: C, 73.30; H, 7.12; N, 6.56.
Embodiment 49
1-(1-methyl piperidine-4-yl)-7-(pyrimidine-5-yl) naphthalene
With 1-(1-methyl piperidine-4-yl)-7-trifluoromethane sulfonyloxy naphthalene (0.304g, 0.819mmol), 5-trimethylammonium stannyl pyrimidine (0.220g, 0.905mmol), triethylamine (0.55ml, 3.95mmol), lithium chloride (0.107g, 2.53mmol), chlorination two (triphenylphosphine) palladium (0; 029g, 0.041mmol) and the mixture heating up to 115 of butylated hydroxyl toluene (BHT, about 0.01g, antioxidant) in dimethyl formamide (15ml) ℃ and keeping 1 hour.The cooling reaction solution also dilutes with ethyl acetate.Mixture extracts with the mixture of 1N lithium chloride (25ml) and 1NNaOH (3ml), 1N lithium chloride and salt solution, and organic phase also concentrates with calcium sulfate is dry.Resistates carries out flash chromatography and separates (1 * 2.5 inch, with the filling of 75% ethyl acetate/hexane) on silica gel.Wash-out is performed as follows: 75% ethyl acetate/hexane, 225ml, zero; Ethyl acetate, 200ml, zero, 1% methanol/ethyl acetate, 200ml, zero; 5% methanol/ethyl acetate, 300ml, zero; With 7% methyl alcohol/1% triethylamine/ethyl acetate, 250ml, 0.130g (52%) brown spumescence 1-(1-methyl piperidine-4-yl)-7-pyrimidine-5-base naphthalene.Sample and ether development obtain white crystal, and mp121.5-123 ℃, 1H NMR (250MHz, CDCl 3) δ 9.27 (s, 1H), 9.08 (s, 2H), 8.26 (s, 1H), 8.03 (d, J=8.5Hz, 1H), 7.78 (dd, J=3,6.5Hz, 1H), 7.69 (dd, J=1.5,8.5Hz, 1H), and 7.57-7.50 (m, 2H), 3.36 (symm, 1H), 3.09 (brd, J=12Hz, 2H), 2.40 (s, 3H), 2.28 (symm, 2H), 2.06-1.90 (m, 4H).C 20H 21N 3The ultimate analysis calculated value: C, 79.17; H, 6.98; N, 13.85.Measured value: C, 78.46; H, 7.14; N, 13.89.HRMS m/e303.1731 surveys m/e303.1700
Embodiment 50
1-(1-methyl piperidine-4-yl)-7-(3-methoxyphenyl) naphthalene
With 1-(1-methyl piperidine-4-yl)-7-trifluoromethane sulfonyloxy naphthalene (0.264g, 0.712mmol), 3-trimethylammonium stannyl methyl-phenoxide (0.212g, 0.783mmol), triethylamine (0.476ml, 3.42mmol), lithium chloride (0.093g, 2.21mmol), chlorination two (triphenylphosphine) palladium (0.025g, 0.036mmol) and the mixture heating up to 115 of butylated hydroxyl toluene (BHT, about 0.01g, antioxidant) in dimethyl formamide (12.5ml) ℃ and keeping 2 hours.The cooling reaction solution also dilutes with ethyl acetate.Mixture extracts with the mixture of 1N lithium chloride (25ml) and 1NNaOH (3ml), 1N lithium chloride and salt solution, and organic phase also concentrates with calcium sulfate is dry.Resistates carries out flash chromatography and separates (1 * 2.5 inch, with the filling of 75% ethyl acetate/hexane) on silica gel.Wash-out is performed as follows: 75% ethyl acetate/hexane, 300ml, zero; Ethyl acetate, 200ml, 0.104g yellow oil.Distill this oil (ball-ball), collect 3 cut: 25-143 ℃ (1mmHg), 0.037g is defined as 1-(1-methyl piperidine-4-yl)-7-methylnaphthalene; 143-168 ℃ (1mmHg), the 0.008g mixed fraction; 168-200 ℃, 0.049g (21%) 1-(1-methyl piperidine-4-yl)-7-(3-methoxyphenyl) naphthalene, glassy yellow oily matter, 1H NMR (250MHz, CDCl 3) δ 8.26 (s, 1H), 7.94 (d, J=8.5Hz, 1H), 7.77-7.70 (m, 2H), 7.47-7.40 (m, 3H), 7.32, (d, J=7.5Hz, 1H), 7.27-7.25m, 1H, quilt 1H NMR solvent is partly fuzzy), 6.96 (dd, J=2.5,8.5Hz, 1H), 3.92 (s, 3H), 3.38 (symm, 1H), 3.07 (brd, J=11.5Hz, 2H), 2.39 (s, 3H), 2.25 (dt, J=3.5,11Hz, 2H), 2.08-1.89 (m, 4H).This product is dissolved in the chloroform and with HCl (gas) bubbling by this solution.Except that desolvating and resistates and ether development being obtained hydrochloride, mp212-214 ℃.C 23H 25The ultimate analysis calculated value of NHCl: C, 75.09; H, 7.12; N, 3.81.Measured value: C, 75.22; H, 7.44; N, 4.19.
Embodiment 51
1-(methyl piperidine-4-yl)-7-(pyridin-3-yl) naphthalene
With 1-(1-methyl piperidine-4-yl)-7-trifluoromethane sulfonyloxy naphthalene (0.250g, 0.67mmol), 5-trimethylammonium stannyl pyridine (0.227g, 0.94mmol), triethylamine (0.448ml, 3.22mmol), lithium chloride (0.093g, 2.21mmol), chlorination two (triphenylphosphine) palladium (0.025g, 0.036mmol) and the mixture heating up to 115 of butylated hydroxyl toluene (BHT, about 0.01g, antioxidant) in dimethyl formamide (12.5ml) ℃ and keeping 2.5 hours.The cooling reaction solution also dilutes with ethyl acetate.Mixture extracts with the mixture of 1N lithium chloride (25ml) and 1NNaOH (3ml), 1N lithium chloride and salt solution, and organic phase also concentrates with calcium sulfate is dry.Resistates carries out flash chromatography and separates (1 * 3 inch, with the filling of 75% ethyl acetate/hexane) on silica gel.Wash-out is performed as follows: 75% ethyl acetate/hexane, 300ml, zero; Ethyl acetate, 200ml, zero; 4% methyl alcohol/1% triethylamine/ethyl acetate, 300ml, the brown oily 1-of 0.091g (45%) (1-methyl piperidine-4-yl)-7-(pyridin-3-yl) naphthalene.This product is further purified by ball-ball distillation, obtains orange oily product under 220 ℃ (1mmHg), 1H NMR (250MHz, CDCl 3) δ 8.99 (m, 1H), 8.66 (dd, J=1.5,5Hz, 1H), 8.26 (s, 1H), 8.06-7.97 (m, 3H), 7.81-7.76 (m, 1H), 7.70 (dd, J=1.5,8.5Hz, 1H), 7.52-7.40 (m, 3H), 3.38 (symm, 1H), 3.10 (brd, J=11.5Hz, 2H), 2.41 (s, 3H), 2.28 (symm, 2H), 2.10-1.93 (m, 4H).Product is dissolved in the chloroform and with HCl (gas) bubbling enters in this solution.Removing desolvates and develop resistates with ether obtains 0.08g amorphous solid shape hydrochloride, melting range 130-160 ℃.C 21H 22N 22HCl2.5H 2The ultimate analysis calculated value of O: C, 60.00; H, 6.95; N, 6.66.Measured value: C, 59.49; H, 6.85; N, 6.35.
Embodiment 52
The general procedure of synthetic 1-(4-methylpiperazine-1-yl)-7-(1,2,4-oxadiazole-5-yl) naphthalene
Add solid hydroxylamine hydrochloride (2.5 equivalent) in 0 ℃ of stirred solution of sodium (2.5 equivalent) in dehydrated alcohol (25ml/g sodium), the gained mixture stirred 30 minutes under nitrogen in room temperature.Add suitable nitrile (1.0 equivalent) then, one night of reaction mixture (16 hours) that reflux produced.Reaction mixture is used Celite then Filter, reduction vaporization filtrate obtains corresponding rough amidoxim, is directly used in the next step immediately.
In the stirred solution of rough amidoxim (2.0 equivalent) in anhydrous tetrahydro furan (20ml/g amidoxim), add sodium hydride (2.2 equivalent), the reaction soln that is produced in refluxed under nitrogen heating 30 minutes.Cooled reaction solution adds 1-(4-methylpiperazine-1-yl) naphthalene-solution of 7-carboxylic acid benzyl ester (1.0 equivalent) in anhydrous tetrahydro furan (10mg/g1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid benzyl ester).Heated the gained reaction soln 2 hours in refluxed under nitrogen then.The reaction soln that reduction vaporization produced, resistates use silica gel (50g/g resistates) to carry out chromatographic separation, carry out wash-out with suitable solvent system, obtain corresponding 1-(4-methylpiperazine-1-yl)-7-(1,2,4-oxadiazole-5-yl) naphthalene.
Use this general procedure, be prepared as follows compound:
A.7-(3-(4-Chlorophenylmethyl)-1,2,4-oxadiazole-5-yl)-1-(4-methylpiperazine-1-yl) naphthalene
Use sodium (5.6g, 0.25mol), oxammonium hydrochloride (17.3g, 0.25mol) and (4-chloro-phenyl-) acetonitrile (15.1g, 0.10mol) and next preparation (4-chloro-phenyl-) acetyl amidoxim (the acetamidoxime) (18.5g as mentioned above that presses of methyl alcohol (150ml), 0.10mol, 100%).
Use (4-chloro-phenyl-) acetyl amidoxim (0.374g, 2.00mmol), sodium hydride (60% oil suspension, 0.093g, 2.3mmol), 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid benzyl ester (0.360g, 1.00mmol) and anhydrous tetrahydro furan (12ml altogether) come by forming title compound as mentioned above.Use 10% methanol/ethyl acetate wash-out to carry out chromatogram purification and obtain cream-coloured spumescence title compound (0.105g, 0.25mmol, 25%):
13C NMR (acetone, d 6) δ 176.7,170.8,150.0,137.4,135.8,133.1,131.6,130.6,129.7,129.3,128.9,125.2,124.9,124.8,121.9,117.9,55.2,51.3,44.2,31.9; LRMS (m/z, relative intensity) 420 ([M +, 37Cl], 36), 419 (46), 418 ([M +, 35Cl], 100), 403 (14), 151 (86), 113 (77); C 24H 23ClN 4The HRMS calculated value of O: 418.1555 measured values: 418.1543.
B.1-(4-methylpiperazine-1-yl)-7-(3-(pyridin-4-yl methyl)-1,2,4-oxadiazole-5-yl) naphthalene
Use sodium (0.253g, 11.5mmol), oxammonium hydrochloride (0.570g, 8.20mmol) and hydrochloric acid (4-pyridyl) acetonitrile (0.500g, 3.20mmol) and next preparation (4-pyridyl) the acetyl amidoxim (0.580g,＞100%) as mentioned above of pressing of methyl alcohol (5ml).
Use (4-pyridyl) acetyl amidoxim (0.580g, 3.2mmol), sodium hydride (60% oil suspension, 0.160g, 4.0mmol), 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid benzyl ester (0.600g, 1.66mmol) and anhydrous tetrahydro furan (16ml altogether) come by forming title compound as mentioned above.Use 3% ethanol/methylene wash-out to carry out chromatogram purification and obtain cream-coloured spumescence title compound (0.075g, 0.19mmol, 12%):
13C NMR (CD 3OD) δ 176.4,168.8, and 150.5,149.0,148.9,146.4,136.8,129.4,128.7,128.1,124.7,124.6,123.2,122.5,120.2,116.1,55.0,52.4,44.8,30.9; FAB LRMS (m/z, relative intensity) 387 (32), 386 (M +, 100).C 23H 23N 5O0.33NH 2The ultimate analysis calculated value of OH (azanol): C, 69.70; H, 6.10; N, 18.84.Measured value: C, 69.89; H, 6.00; N, 18.4.
C.1-(4-methylpiperazine-1-yl)-7-(3-pyridin-3-yl methyl)-1,2,4-oxadiazole-5-yl) naphthalene
Use sodium (0.183g, 7.96mmol), (0.570g is 8.20mmol) with (3-pyridyl) acetonitrile (0.375g for oxammonium hydrochloride, 3.17mmol) and next preparation (3-pyridyl) the acetyl amidoxim (0.50g,＞100%) as mentioned above of pressing of methyl alcohol (5ml).
Use (3-pyridyl) acetyl amidoxim (0.50g, 3.17mmol), sodium hydride (60% oil suspension, 0.282g, 7.0mmol), 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid benzyl ester (0.576g, 1.60mmol) and anhydrous tetrahydro furan (16ml altogether) come by forming title compound as mentioned above.Use 6% ethanol/methylene wash-out to carry out chromatogram purification and obtain cream-coloured spumescence title compound (0.160g, 0.42mmol, 26%):
13C NMR (CD 3OD) δ 176.4,169.5, and 150.5,149.2,147.4,137.6,136.8,132.5,129.4,128.7,128.1,124.5,123.9,123.2,123.2,120.3,116.1,55.0,52.4,44.7,28.9; LRMS (m/z, relative intensity) 386 (18), 385 (M +, 61), 370 (63), 342 (100), 315 (29), 287 (22), 71 (59); C 23H 23N 5The HRMS calculated value of O: 385.1898 measured values: 385.1906C 23H 23N 5O0.5H 2The ultimate analysis calculated value of O: C, 70.03; H, 6.13; N, 17.75.Measured value: C, 69.67; H, 6.12; N, 17.71.
D.1-(4-methylpiperazine-1-yl)-7-(3-pyridine-2-ylmethyl)-1,2,4-oxadiazole-5-yl) naphthalene
Use sodium (0.183g, 7.96mmol), (0.570g is 8.20mmol) with (2-pyridyl) acetonitrile (0.375g for oxammonium hydrochloride, 3.17mmol) and next preparation (2-pyridyl) the acetyl amidoxim (0.55g,＞100%) as mentioned above of pressing of methyl alcohol (5ml).
Use (2-pyridyl) acetyl amidoxim (0.55g, 3.17mmol), sodium hydride (60% oil suspension, 0.282g, 7.0mmol), 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid benzyl ester (0.576g, 1.60mmol) and anhydrous tetrahydro furan (16ml altogether) come by forming title compound as mentioned above.Use 6% ethanol/methylene wash-out to carry out chromatogram purification and obtain cream-coloured spumescence title compound (0.122g, 0.32mmol, 20%): LRMS (m/z, relative intensity) 386 (18), 385 (M +, 100); 370 (27), 182 (59), 154 (45); C 23H 23N 5The HRMS calculated value of O: 385.1898, measured value: 385.1910.
E.7-(3-(4-chloro-phenyl-)-1,2,4-oxadiazole-5-yl)-1-(4-methylpiperazine-1-yl) naphthalene
Use sodium (0.24g, 10.4mmol), oxammonium hydrochloride (0.70g, 10mmol) and 4-benzyl chloride nitrile (0.548g, 3.98mmol) and methyl alcohol (10ml) come by preparation (4-chloro-phenyl-) amidoxim (0.70g, 100%) as mentioned above.
Use (4-chloro-phenyl-) amidoxim (0.70g, 3.97mmol), sodium hydride (60% oil suspension, 0.176g, 4.4mmol), 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid benzyl ester (0.720g, 2.0mmol) and anhydrous tetrahydro furan (25ml altogether) come by forming title compound as mentioned above.Use 6% ethanol/methylene wash-out to carry out chromatogram purification and obtain cream-coloured spumescence title compound (0.164g, 0.41mmol, 20%): 13C NMR (CDCl 3) δ 176.4,168.2,151.0,137.5,136.8,129.5,129.2,128.9,128.5,125.8,125.3,124.0,123.2,120.7,116.1,55.5,53.2,46.2; LRMS (m/z, relative intensity) 406 ((M +, 37Cl), 52), 405 (45), 404 ((M +, 35Cl), 100), 319 (34), 70 (75); C 23H 21N 4The HRMS calculated value of O: 404.1399, measured value: 404.1386.C 23H 21N 4The ultimate analysis calculated value of O: C68.23; H, 5.23; N, 13.84; Measured value: C, 68.12; H, 5.31; N, 13.96.
F.7-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl)-1-(4-methylpiperazine-1-yl) naphthalene
Use sodium (0.24g, 10.4mmol), oxammonium hydrochloride (0.70g, 10mmol) and acetonitrile (1.2ml, 23.0mmol) and methyl alcohol (10ml) by preparing acetyl amidoxim (0.80g,＞100%) as mentioned above.
Use acetyl amidoxim (0.80g, 10mmol), sodium hydride (60% oil suspension, 0.174g, 4.4mmol), 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid benzyl ester (0.760g, 2.1mmol) and anhydrous tetrahydro furan (25ml altogether) come by forming title compound as mentioned above.Use 6% ethanol/methylene wash-out to carry out chromatogram purification and obtain cream-coloured amorphous solid shape title compound (0.120g, 0.39mmol, 19%):
13C NMR (CD 3OD) δ 177.2,169.1, and 151.9,138.1,130.8,130.0,129.5,125.8,124.6,124.5,121.8,117.4,56.4,53.9,46.2,11.5; LRMS (m/z, relative intensity) 309 (17), 308 (M +, 100), 293 (11), 223 (20), 71 (39); C 18H 20N 4The HRMS calculated value of O: 308.1633, measured value: 308.1617.C 18H 20N 4O0.25H 2The ultimate analysis calculated value of O; C, 69.10; H, 6.60; N, 17.91.Measured value: C, 69.24; H, 6.55; N, 17.79.
G.7-(3-(4-chlorophenoxy methyl)-1,2,4-oxadiazole-5-yl)-1-(4-methylpiperazine-1-yl) naphthalene
Use sodium (0.24g, 10.4mmol), oxammonium hydrochloride (0.72g, 10mmol) and (4-chlorophenoxy) acetonitrile (0.67g, 4.0mmol) and methyl alcohol (5ml) come by preparation (4-chlorophenoxy) acetyl amidoxim (0.85g,＞100%) as mentioned above.
Use (4-chlorophenoxy) acetyl amidoxim (0.85g, 4.00mmol), sodium hydride (60% oil suspension, 0.190g, 4.7mmol), 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid benzyl ester (0.720g, 2.00mmol) and anhydrous tetrahydro furan (25ml altogether) come by forming title compound as mentioned above.Use ethyl acetate/methanol/triethylamine (65: 1: 1) wash-out to carry out chromatogram purification and obtain cream-coloured spumescence title compound (0.238g, 0.55mmol, 27%): 13C NMR (CDCl 3) δ 177.0,167.2,156.6,151.0,136.8,129.6,129.5,128.9,128.4,126.8,125.5,123.9,123.3,120.3,116.4,116.1,61.6,55.4,53.2,46.1; LRMS (m/z, relative intensity) 436 ((M +, 37Cl), 17), 435 (12), 434 ((M +, 35Cl), 100), 71 (97), 70 (84); C 24H 23ClN 4O 2The HRMS calculated value: 434.1504; Measured value: 434.1490.C 24H 23ClN 4O0.5H 2The ultimate analysis calculated value of O: C, 64.93; H, 5.45; N, 12.62; Measured value: C, 64.74; H, 5.46; N, 12.38.
H.7-(3-(1, the 1-dimethyl ethyl)-1,2,4-oxadiazole-5-yl)-1-(4-methylpiperazine-1-yl) naphthalene
Use sodium (0.112g, 4.9mmol), oxammonium hydrochloride (0.35g, 5mmol) and trimethylacetonitrile (0.334g, 2.0mmol) and methyl alcohol (5ml) by preparing pivalyl amidoxim (0.35g, 100%) as mentioned above.
Use pivalyl amidoxim (0.35g, 2.00mmol), sodium hydride (60% oil suspension, 0.090g, 2.2mmol), 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid benzyl ester (0.360g, 1.00mmol) and anhydrous tetrahydro furan (15ml altogether) come by forming title compound as mentioned above.Use ethyl acetate/methanol/triethylamine (40: 1: 1) wash-out to carry out chromatogram purification and obtain light yellow spumescence title compound (0.168g, 0.48mmol, 48%): 1HNMR (CDCl 3) δ 9.00 (brs, 1H), 8.16 (dd, J=1.6 and 8.6Hz, 1H), 7.94 (d, J=8.6Hz, 1H), 7.59-7.49 (m, 2H), 7.18 (dd, J=1.1 and 7.2Hz, 1H), 3.23 (brm, 4H), 2.84 (brm, 4H), 2.51 (s, 3H), 1.49 (s, 9H); LRMS (m/z, relative intensity) 351 (18), 350 (M +, 100), 335 (10), 293 (29), 182 (29), 71 (50), 70 (46); C 21H 26N 4The HRMS calculated value of O: 350.2101; Measured value: 350.2111.C 21H 26N 4OH 2The ultimate analysis calculated value of O: C, 68.45; H, 7.66; N, 15.20.Measured value: C, 68.14; H, 7.32; N, 14.91.
I.7-(3-(3-Chlorophenylmethyl)-1,2,4-oxadiazole-5-yl)-1-(4-methylpiperazine-1-yl) naphthalene
Use sodium (0.120g, 5.2mmol), oxammonium hydrochloride (0.35g, 5.0mmol) and (3-chloro-phenyl-) acetonitrile (0.303g, 2.0mmol) and methyl alcohol (5ml) come by preparation (3-chloro-phenyl-) acetyl amidoxim (0.42g,＞100%) as mentioned above.
Use (3-chloro-phenyl-) acetyl amidoxim (0.42g, 2.00mmol), sodium hydride (60% oil suspension, 0.093g, 2.3mmol), 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid benzyl ester (0.360g, 1.00mmol) and anhydrous tetrahydro furan (12ml altogether) come by forming title compound as mentioned above.Use 10% methanol/ethyl acetate wash-out to carry out chromatogram purification and obtain light yellow spumescence title compound (0.105g, 0.25mmol, 25%): 13C NMR (CDCl 3) δ 176.4,169.6,150.9,137.5,136.6,134.5,129.9,129.5,129.3,128.7,128.3,127.4,127.3,125.2,123.9,123.2,120.7,116.0,55.5,53.2,46.1,32.1; LRMS (m/z, relative intensity) 420 ((M +, 37Cl), 29), 419 (32), 418 ((M +, 35Cl), 100), 403 (14); 350 (53), 293 (28), 182 (39), 154 (39), 71 (95), 70 (63); C 24H 23ClN 4The HRMS calculated value of O: 418.1555, measured value: 418.1583.C 24H 23ClN 4O0.5H 2The ultimate analysis calculated value of O: C, 67.36; H, 5.65; N, 13.09.Measured value: C, 67.28; H, 5.54; N, 12.95.
J.7-(3-phenyl propyl-1,2,4-oxadiazole-5-yl)-1-(4-methylpiperazine-1-yl) naphthalene
Use sodium (0.235g, 10.2mmol), (0.70g is 10.1mmol) with 4-phenylbutyronitrile (0.58g for oxammonium hydrochloride, 4.0mmol) and methyl alcohol (6ml) come by preparing 4-phenyl butyryl amidoxim (butyroamidoxime) (0.79g,＞100%) as mentioned above.
Use 4-phenyl butyryl amidoxim (0.79g, 4.0mmol), sodium hydride (60% oil suspension, 0.210g, 5.2mmol), 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid benzyl ester (0.720g, 2.00mmol) and anhydrous tetrahydro furan (20ml altogether) come by forming title compound as mentioned above.Use 4-10% methanol/ethyl acetate gradient elution to carry out chromatogram purification and obtain faint yellow amorphous solid shape title compound (0.363g, 0.88mmol, 44%): 1H NMR (acetone-d 6) δ 9.01 (brs, 1H), 8.11 (dd, J=8.6 and 1.7Hz, 1H), 8.04 (d, J=8.5Hz, 1H), 7.66 (d, J=8.2Hz, 1H), 7.56 (t, J=8.2Hz, 1H), 7.32-7.15 (m, 6H), 3.12 (brm, 4H), 2.83 (t, J=7.4Hz, 2H), 2.77 (t, J=7.4Hz, 2H), 2.70 (brm, 4H), 2.35 (s, 3H), 2.18-2.08 (m, 2H); 13C NMR (CDCl 3) δ 176.3,171.9,151.8,142.4,137.4,130.4,129.6,129.3,129.1,129.0,126.6,125.4,124.4,123.9,121.6,116.8,56.1,53.9,46.2,35.5,25.9; FAB LRMS (m/z, relative intensity) 413 (MH +, 100).
Embodiment 53
Ammonia is separated the general method of 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid
At room temperature (0.270g 1.00mmol) directly adds solid carbonyl dimidazoles (0.178mg, 1.10mmol, 1.1 equivalents) in the stirred solution in anhydrous tetrahydro furan (5ml) to 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid.At room temperature in nitrogen, stirred the reaction soln that produced 3 hours.Add suitable amine (1.1mmol, 1.1 equivalents) then, the reaction soln that stirring at room produced under nitrogen 16 hours.The saturated solution that adds sodium bicarbonate is with the aqueous mixture (2 * 25ml) that ethyl acetate extraction produced.Merge organic extract liquid, dry (MgSO 4) and reduction vaporization.Resistates uses silica gel (about 50g) and proper solvent system to carry out column chromatography to separate and obtain corresponding 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid amides.
Use this method to prepare following compounds:
A.N-(2-(indol-3-yl) ethyl)-1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid amides
Tryptamines is used amine.Use 20% methanol/ethyl acetate wash-out to carry out chromatographic separation and obtain white foam shape title compound (63%): Rf=0.20 (20% methanol/ethyl acetate);
13C NMR (acetone-d 6) δ 167.9,151.7,137.7,136.8,132.7,129.2,128.9,128.6,128.3,124.6,124.3,123.6,123.3,122.0,119.3,119.3,116.0,113.4,112.1,56.0,53.8,46.3,41.5,26.3; LRMS (m/z, relative intensity) 412 (M +, 100), 269 (41), 143 (60), 130 (36), 71 (43), 70 (30); C 26H 28N 4The HRMS calculated value of O: 412.2229, measured value: 412.2305.
B.1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid amides
Ammonia is used amine.Extractive reaction liquid directly obtains white foam shape title compound (35%):
1H NMR (CDCl 3) δ 8.71 (brs, 1H), 7.89 (d, J=8.5Hz, 1H), 7.85 (dd, J=1.6 and 8.5Hz, 1H), 7.59 (brd, J=8.1Hz, 1H), 7.51 (t, J=7.3Hz, 1H), 7.17 (d, J=1.1 and 7.2Hz, 1H), 6.4-5.8 (br, 2H), 3.17 (brm, 4H), 2.76 (brm, 4H), 2.45 (s, 3H); 13C NMR (CDCl 3) δ 170.0,150.8,136.4,130.1,129.0,128.2,128.0,123.8,123.2,115.7,55.5,53.2,46.1; C 16H 19N 3The HRMS calculated value of O: 269.1530, measured value: 269.1542.
C.N-(4-pyridylmethyl)-1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid amides
4-(amino methyl) pyridine is used amine.Use methylene chloride/ammonium hydroxide (10: 4: 0.4) wash-out to carry out chromatographic separation and obtain imidazoles acyl (imidazoyl) salt title compound.This material is dissolved in the methylene dichloride (25ml), and uses Na 2CO 3(1M, 2 * 20ml) extract this solution to solution.Ethyl acetate layer drying (K 2CO 3) and reduction vaporization obtain weak yellow foam shape title compound (35%): LRMS (m/z, relative intensity) 360 (M +, 50), 345 (46), 317 (100), 290 (27), 225 (27), 154 (35), 71 (66), 70 (48); C 22H 24N 4The HRMS calculated value of O: 360.1945, measured value: 360.1932.C 22H 24N 4OH 2The ultimate analysis calculated value of O: C, 69.82; H, 6.92; N, 14.80.Measured value: C, 69.82; H, 6.91; N, 14.53.
D.N-(3-pyridylmethyl)-1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid amides
3-(amino methyl) pyridine is used amine.Use methylene chloride/ammonium hydroxide (20: 1: 0.1) wash-out to carry out chromatographic separation and obtain imidazoles acyl salt title compound.This material is dissolved in the methylene dichloride (25ml), and uses Na 2CO 3(1M, 2 * 20ml) extract this solution to solution.Ethyl acetate layer drying (K 2CO 3) and reduction vaporization obtain white amorphous solid shape title compound (17%): 13C NMR (CD 3OD) δ 170.7,160.7, and 151.9,149.2,148.6,137.6,137.2,137.0,132.0,130.0,129.5,129.2,125.2,125.2,124.4,116.9,56.4,53.8,46.2,42.2; LRMS (m/z, relative intensity) 360 (M +, 36), 345 (43), 317 (100), 290 (30), 242 (30), 208 (35), 71 (75); C 22H 24N 4The HRMS calculated value of O: 360.1945, measured value: 360.1946.
E.N-(2-pyridylmethyl)-1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid amides
2-(amino methyl) pyridine is used amine.Use methylene chloride/ammonium hydroxide (9: 1: 0.1) wash-out to carry out chromatographic separation and obtain imidazoles acyl salt title compound.This material is dissolved in the methylene dichloride (25ml), and uses Na 2CO 3(1M, 2 * 20ml) extract this solution to solution.Ethyl acetate layer drying (K 2CO 3) and reduction vaporization obtain faint yellow oily title compound (19%): 13C NMR (CD 3OD 3) δ 170.7,159.5,151.9,149.8,149.6,138.9,137.8,132.1,130.0,129.5,129.1,125.2,124.4,124.0,122.7,116.9.56.4,53.8,46.2,46.0; LRMS (m/z, relative intensity) 360 (M +, 100), 345 (71), 317 (38), 290 (48), 182 (64), 71 (89); C 22H 24N 4The HRMS calculated value of O: 360.1945, measured value: 360.1932.
F.N-(4-pyridyl ethyl)-1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid amides
2-(2-amino-ethyl) pyridine is used amine.Use 20% methanol/ethyl acetate wash-out to carry out chromatographic separation and obtain imidazoles acyl salt title compound.This material is dissolved in the methylene dichloride (25ml), and uses Na 2CO 3(1M, 2 * 20ml) extract this solution to solution.Ethyl acetate layer drying (K 2CO 3) and reduction vaporization obtain transparent light brown oily title compound (54%): Rf=0.15,20% methanol/ethyl acetate; LRMS (m/z, relative intensity) 374 (M +, 50), 359 (100), 331 (34), 304 (63), 208 (43), 182 (73), 149 (83); C 23H 26N 4The HRMS calculated value of O: 374.2106; Measured value: 374.2111.
Embodiment 54
N-(5-(1, the 1-dimethyl ethyl)-1,2,4-oxadiazole-3-ylmethyl)-1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid amides
At-10 ℃ of down past 1-(4-methylpiperazine-1-yl) naphthalene-7-carboxylic acid amides (0.100g, 0.37mmol) add di-isopropyl lithamide (1.5M tetrahydrofuran solution in the solution in anhydrous tetrahydro furan (5ml), 0.30ml, 0.45mmol, 1.2 equivalent), the gained reaction soln is warmed to room temperature.Add 3-(chloromethyl)-5-(1, the 1-dimethyl ethyl)-1,2 then, 4-oxadiazole (0.078g, 0.45mmol, 1.2 equivalents), the gained reaction soln was refluxed under nitrogen heating 22 hours.Add saturated sodium bicarbonate solution then, with the aqueous mixture (2 * 20ml) that ethyl acetate extraction produced.Merge organic extract liquid, dry (MgSO 4) and reduction vaporization.Resistates uses silica gel (about 25g) to carry out the column chromatography separation and obtains yellow oily title compound (0.035g, 0.09mmol, 23%): Rf=0.40, ethyl acetate/methanol/triethylamine (8: 1: 1) with 5% triethylamine/eluent ethyl acetate; 1H NMR (CDCl 3) δ 8.88 (brs, 1H), 7.84 (s, 2H), 7.54 (d, J=8.0Hz, 1H), 7.46 (brt, J=8.2Hz, 1H), 7.12 (dd, J=1.0 and 7.3Hz), 6.98 (brt, NH), 4.83 (d, J=5.4Hz, 2H), 3.13 (brm, 4H), 2.73 (brm, 4H), 2.40 (s, 3H), 1.43 (s, 9H); LRMS (m/z, relative intensity) 407 (M +, 46), 392 (20), 182 (45), 151 (57), 113 (54), 71 (100), 70 (34); C 23H 29N 5O 2The HRMS calculated value: 407.2315, measured value: 407.2310.
Preparation 1
8-(4-methylpiperazine-1-yl) Betanaphthol
In the stirred solution of 8-amino-beta naphthal (3.28g, 20mmol, Aldrich Chem.Co.) in the 100ml acetonitrile, add NaHCO 3(7.42g, 88mmol), NaI (6.72g, 44mmol) and hydrochloride methyl Dichloroethyl amine (4.32g, 22mmol).Under nitrogen, reacting by heating liquid is to refluxing and restir 2 hours.Reaction mixture is to room temperature then, and stirs a night, uses methylene dichloride: methyl alcohol: the tlc (tlc) of dense ammonium hydroxide (90: 10: 1) shows the bigger product (Rf0.25) of polarity, only contains a small amount of raw material naphthols.Add silica gel (4.5g) and vacuum concentration reaction mixture and obtain exsiccant red-violet colour solid.It is added in silica gel (about 400g) post, with the CH of 2 liters of volumes 2Cl 2, CH 2Cl 2: CH 3OH (40: 1), CH 2Cl 2: CH 3OH: dense NH 4OH (20: 1: 0.1) wash-out is used 4 liters of CH at last 2Cl 2: CH 3OH: dense NH 4OH (10: 1: 0.1) wash-out.Merge suitable fraction and obtain the purple black solid, 5.26g, mp 184-185 ℃.
1H?NMR(CD 3OD)δ2．40(s，3H)，2．72(bs，4H)，3．05(bs，4H)，7．05(d，2H)，7．18(t，1H)，7．45(m，2H)，7．67(d，1H)。Mass spectrum: m/e242 (M +).
Preparation 2
Trifluoromethayl sulfonic acid 8-(4-methylpiperazine-1-yl) naphthalene-2-base ester
Toward 8-(4-methylpiperazine-1-yl) Betanaphthol (5.0g, 20mmol) anhydrous methylene chloride (50ml) be cooled to add triethylamine (20ml) in-78 ℃ the stirred solution, add Trifluoromethanesulfonic anhydride (3.9ml) then.Under-78 ℃ after 1 hour, remove cooling bath, add silica gel (4.5g) and solvent removed in vacuo.The slurry that is produced is added on the 400g silicagel column, uses ethyl acetate: methyl alcohol gradient (100: 0-80: 20) eluted product.Vacuum concentration product fraction obtains title product: 4.32g.
Preparation 3
8-(4-methylpiperazine-1-yl) naphthalene-2-carboxylic acid benzyl ester
Aforesaid compound (34g, 90.8mmol, 1.0 equivalent), benzylalcohol (170ml), chlorination two (triphenyl phosphine) palladium (II) (6.2g, 8.8mmol, 0.1 equivalent), the mixture of lithium chloride (0.44g, 10.5mmol, 0.1 equivalent) and triethylamine (32ml) under carbon monoxide atmosphere (50psi) in 70 ℃ of joltings 6.5 hours.The reaction soln that is produced is directly used silica gel (2kg, wetting in advance with ethyl acetate) to filter and with ethyl acetate (8ml), is obtained light brown spumescence title compound (28.04g, 77.8mmol, 86%) with 5% methanol/ethyl acetate wash-out then. 1H NMR (acetone-D 6) δ 9.00 (d, J=0.7Hz, 1H), 8.04 (dd, J=8.6 and 1.7Hz, 1H), 7.96 (d, J=8.6Hz, 1H), 7.66 (d, J=8.2Hz, 1H), 7.59-7.53 (m, 3H), 7.47-7.36 (m, 3H), 7.22 (dd, J=7.3 and 1.1Hz, 1H), 5.43 (s, 2H), 3.20 (brm, 4H), 2.91 (brm, 4H), 2.54 (s, 3H) LRMS (m/e, relative intensity) 361 (M +, 29).C 23H 24N 2O 2The HRMS calculated value: 360.1839, measured value: 360.1832.
Preparation 4
8-(4-methylpiperazine-1-yl) naphthalene-2-carboxylic acid
With 8-(4-methylpiperazine-1-yl) naphthalene-2-carboxylic acid benzyl ester (0.20g, 5.55mmol) and charcoal carry Pd (OH) (0.11g) mixture in 2ml ethanol in Parr jolting instrument in 50psi hydrogenation 5 hours.With alcohol dilution and with behind the diatomite filtration, solvent removed in vacuo obtains spumescence title product, 138mg.
Preparation 5
1-(1-methyl piperidine-4-yl)-7-trifluoromethane sulfonyloxy naphthalene
In two side-by-side reactions, with 8-bromo-2-Tetralone an intermediate of Sertraline (7.0g, 31.25mmol) and N-bromosuccinimide (5.84g 32.8mmol) sneaks into CCl 4In and refluxed 45 minutes.The cooling reaction solution is used diatomite Celite TMFilter, and merge processing.The saturated NaHCO of organic solution 3The aqueous solution and salt water washing, dry and concentrated with the filter paper that is separated (1PS) then, obtain 14.44g (104% crude product) and be suitable for the further brown solid shape 8-bromo-beta naphthal of reaction.Sample is dissolved in CH 2Cl 2In, use activated carbon treatment, concentrate and develop with hexane, obtain product, mp96-100 ℃, 1H NMR (250MHz, CDCl 3) δ 7.79-7.73 (m, 3H), 7.56 (d, J=4.5Hz, 1H), 7.22-7.14 (m, 3H).C 10H 7The HRMS m/e calculated value of BrO: 221.9680, actual measurement m/e:221.9664.
In two side-by-side reactions, with 8-bromo-beta naphthal (7.22g, 32.5mmol) be dissolved in the tetrahydrofuran (THF) (200ml) and quenching to-78 ℃.Rapidly (1-2 minute) add butyllithium (31.2ml, 74.8mmol) and stirred solution 12 minutes.1-methyl-4-piperidone (4.22ml, 34.2mmol are dissolved in the 10ml tetrahydrofuran (THF)) is added drop-wise in this solution, with the rinsing of 10ml tetrahydrofuran (THF).Reaction solution stirred 30 minutes down in-78 ℃ again.Be warmed to room temperature then.Merge reaction solution and directly be concentrated to and carry out flash chromatography separation (3.5 * 4 inches silica gel load with ethyl acetate) on the silica gel.Wash-out is performed as follows: ethyl acetate, 500ml, zero; 2% methyl alcohol/1% triethylamine/ethyl acetate, 1000ml, zero; 4% methyl alcohol/2% triethylamine/ethyl acetate, 2000ml, zero; 6% methyl alcohol/3% triethylamine/ethyl acetate, 3000ml, the pure 1-of 7.64g (1-methyl-4-hydroxy piperidine-4-yl)-7-hydroxyl naphthalene.With 8% methyl alcohol/4% triethylamine/ethyl acetate, 2000ml continues wash-out, obtains the extra product of 4.32g, and it may be a salt significantly by the impurity from triethylamine, pollutes.Mp with the pure products sample of 1/3 methylate recrystallization Cong diox is 206-208 ℃ (decomposition);
1H NMR (250MHz, DMSO D6) δ 9.63 (s, 1H), 8.20 (d, J=2Hz, 1H), 7.73 (d, J=9Hz, 1H), 7.65 (d, J=8Hz, 1H), 7.47 (d, J=6.5Hz, 1H), 7.18 (t, J=7.5Hz, 1H), 7.02 (dd, J=2.5,9Hz, 1H), 4.96 (s, 1H), 2.70-2.46 (m, 4H, partly fuzzy by the NMR solvent), 2.22 (s, 3H), 2.21-2.00 (m, 4H).Also have two that 1/3 methylate integration is gone out unimodal at δ 5.76 and 3.56 places.C 16H 19NO 20.33CH 4The ultimate analysis calculated value of O: C, 73.29; H, 7.53; N, 5.23.Measured value: 73.61; H, 7.62; N, 5.32.
With 1-(1-methyl-4-hydroxy piperidine-4-yl)-7-hydroxyl naphthalene (7.64g, 29.7mmol) and tosic acid (6.78g, 35.7mmol) the mixture in the Zai diox (250ml) refluxes a night.Removal of solvent under reduced pressure also is dissolved in CH with resistates 2Cl 2In.Naphthols product 1NNaOH, 4NNaOH is that 1NNaOH extracts from this organic phase then.The saturated NaHCO of alkaline water that merges 3The aqueous solution is neutralized to pH8 also with warm chloroform extraction (3x, the violent mechanical stirring of two-phase mixture heats with hot plate simultaneously).The organic phase (still warm) that merges is used the salt water washing, uses CaSO 4Drying, and concentrated 5.01g (productive rate is 83% concerning this step) brown solid shape 1-(1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-the yl)-7-hydroxyl naphthalene that obtains.The mp of the sample of recrystallization is 182.5-184 ℃ from ethyl acetate;
1H?NMR(250MHz，CDCl 3)δ9．15(s，1H)，7．98(d，J=2．5Hz，1H)，7．69(d，J=9Hz，1H)，7．65(d，J=8Hz，1H)，7．25-7．12(m，2H)，7．03(dd，J=2．5，9Hz，1H)，5．70(symm，1H)，3．32(symm，2H)，2．92(t，J=6Hz，2H)，2．70-2．60(m，2H)，2．66(s，3H)。C 16H 17NO0.25H 2The ultimate analysis calculated value of O: C, 78.82; H, 7.23; N, 5.74.Measured value: C, 78.81; H, 7.21; N, 5.83.
Handle under the dehydration conditions that the impure 1-of 4.32g (1-methyl-4-hydroxy piperidine-4-yl)-7-hydroxyl naphthalene is identical in the above, obtain the 1.13g crude product.Recrystallization gets 0.855g white crystalline 1-(1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-yl)-7-hydroxyl naphthalene in ethyl acetate.To top two the step obtain 5.865g altogether, overall yield is 39%.
(5.865g, 24.54mmol), 20% carbon carries palladium (5.9g), 6.5 hours (initial pressures: 40psi) of mixture hydrogenation of alcohol (210ml) and acetate (30ml) with 1-(1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-yl)-7-hydroxyl naphthalene.Mixture should fill up through diatomite filtration and with the abundant rinsing of methyl alcohol.Removal of solvent under reduced pressure is also used NaHCO 3In the saturated aqueous solution and resistates.Mixture is with hot chloroform extraction (3x) and with warm dichloromethane extraction (1x).The organic phase that merges (still hot) is with salt solution (being preheating to the uniform temp of chloroformic solution, about 60 ℃) washing, and is dry and concentrated with calcium sulfate, obtains 2.0g brown solid product.Top supercarbonate water is concentrated into dried.Resistates also filters with hot chloroform extraction.Use methylene dichloride successively, ethanol and repeat the extraction heat process with chloroform once more.Concentrate the solution that merges, obtain other 3.26g brown solid.In this way, obtain 5.26g (89%) 1-(1-methyl piperidine-4-yl)-7-hydroxyl naphthalene.This material is suitable for the not purified next step that is used for.Having mp from the sample of methyl alcohol recrystallize is 196.5-199 ℃; 1H NMR (250MHz, CDCl 3) δ 7.76 (d, J=9Hz, 1H), 7.62 (d, J=8Hz, 1H), 7.40 (d, J=2Hz, 1H), 7.26 (symm, partly fuzzy by the NMR solvent, 2H), 7.09 (dd, J=2.5,9Hz, 1H), 3.26-3.08 (m, 3H), 2.42 (s, 3H), 2.35-2.20 (m, 2H), 2.16-1.92 (m, 4H).C 16H 19The ultimate analysis calculated value of NO: C, 79.63; H, 7.94; N, 5.80.Measured value: C, 79.22; H, 8.18; N, 5.83.
(3.47g, 14.4mmol) (9.03ml 64.8mmol) handles and is quenched to-78 ℃ to the solution in methylene dichloride (150ml) with triethylamine with 1-(1-methyl piperidine-4-yl)-7-hydroxyl naphthalene.(3.03ml 18.0mmol) is added drop-wise in the reaction solution, uses the 10ml dichloromethane with Trifluoromethanesulfonic anhydride (Triflic anhydride).Reaction solution is warmed to room temperature and stirs a night.Be distributed between methylene dichloride and the saturated sodium bicarbonate aqueous solution with the nitrogen gas stream concentration of reaction solution and with resistates.Separate each phase, the calcium sulfate drying is used in organic phase salt water washing, and concentrates.Resistates carries out flash chromatography on silica gel (2 * 3 inches, with the filling of 75% ethyl acetate/hexane) separates.Wash-out is performed as follows: 75% ethyl acetate/hexane, 500ml, zero; Ethyl acetate, 600ml, zero; 2% methyl alcohol/1% triethylamine/ethyl acetate, 600ml, zero; 5% methyl alcohol/2% triethylamine/ethyl acetate, 600ml, 2.74g (51%) 1-(1-methyl piperidine-4-yl)-7-trifluoromethane sulfonyloxy naphthalene is suitable for the further light brown crystalline solid of reaction.From the mp of the sample of ethyl acetate/hexane recrystallization is 144-146 ℃;
1H?NMR(250MHz，CDCl 3)δ7．96-7．91(m，2H)，7．76(dd，J=2．5，7Hz，1H)，7．58-7．51(m，2H)，7．36(dd，J=2．5，9Hz，1H)，3．25-3．12(m，3H)，2．48(s，3H)，2．37(symm，2H)，2．19-1．95(m，4H)。C 17H 18F 3NO 3The HRMS m/e calculated value of S: 373.0954 actual measurement m/e:373.0898.
The synthesizing of intermediate that is used for the foregoing description is being prepared as follows explanation.
Preparation 6
7-hydroxyl-1-(4-methyl isophthalic acid-piperazinyl)-3, the 4-dihydronaphthalene
(2.2ml 19.83mmol) is dissolved among the anhydrous THF (90ml) and quenching to 0 ℃ with 7-hydroxyl-α-Tetralone an intermediate of Sertraline (1.0g, 6.17mmol, Corey andEstreicher, Tetrahedron Lett., 1981,22,603) and 1-methylpiperazine.Allow TiCl 4(0.91ml 8.3mmol) enters the reaction solution through syringe from the reactor side, thereby vigorous reaction takes place, and it is orange red that solution is become.Mixture is warmed to room temperature and stirred 1.5 hours.Add 2: 1 mixtures (90ml) of entry and dense ammonium hydroxide, use the ethyl acetate extraction mixture.Organic phase CaSO 4Dry and concentrated, obtain the rough enamine of 1.48g, need not to characterize immediately and use.(this enamine is to the chromatography instability, but 1Enamine vinyl proton characteristic signal occurs really at the 5.28ppm place among the HNMR, and coupling constant is 4.7Hz.)
Preparation 7
7-hydroxyl-1-(4-methyl isophthalic acid-piperazinyl) naphthalene
10% charcoal is carried palladium (1.16g) and 7-hydroxyl-1-(4-methyl isophthalic acid-piperazinyl)-2,3-dihydronaphthalene (1.48g, 6.06mmol) slurryization and refluxing 16.5 hours in toluene (100ml).Cooling mixture filters and concentrates.Product is used purified by flash chromatography on silica gel (1 * 6 inch).Using 50% ethyl acetate/hexane, is 100% eluent ethyl acetate then, obtains 0.51g (34%) baby pink spumescence title product.The recrystallization sample obtains the cream-colored solid that is used to analyze from ether: mp 184-185 ℃, and C 15H 18N 2The ultimate analysis calculated value of O: C, 74.35; H, 7.49; N, 11.56.Measured value: C, 74.05; H, 7.03; N, 11.42.
Preparation 8
7-trimethylammonium stannyl-1-(4-methyl isophthalic acid-piperazinyl) naphthalene
With 7-trifluoromethyl sulfonyloxy-1-(4-methyl isophthalic acid-piperazinyl) naphthalene (2.0g, 5.34mmol), hexamethylditin (1.92g, 5.86mmol), lithium chloride (0.68g, 16mmol), four (triphenyl phosphine) palladium (0.24g, 0.21mmol) and butylated hydroxyl toluene (several crystal, antioxidant) in no Shui diox (50ml), mix and refluxed 45 minutes.Cooling mixture also uses saturated ammonium chloride (50ml) to stop.With extracted with diethyl ether mixture (2x) and the organic phase that merges with the salt water washing, use dried over mgso, concentrated brown oil.Upward carry out the flash chromatography separation at silica gel (2 * 4 inches) and obtain slowly solidified light brown oily title product of 0.77g (37%) with 50% ethyl acetate/hexane wash-out.Product is applicable to following reaction but non-analytical pure: 1HNMR δ 8.36 (s, with the Sn coupling, 1H), 7.80 (d, J=8Hz, 1H), and 7.61-7.51 (m, 2H), 7.40 (t, J=8Hz, 1H), 7.09 (dd, J=1,7.5Hz, 1H), 3.2 (brs, 4H), 2.75 (brs, 4H), 2.46 (s, 3H), 0.39 (s, with the Sn coupling, 55.0 and 52.5Hz, 9H).
Preparation 9
5-chloromethyl-3-phenyl-1,2, the 4-oxadiazole
With benzoyl amidoxim (0.77g, 5.68mmol) and triethylamine (0.95ml, 0.82mmol) solution in toluene (10ml) at room temperature handled 30 minutes with 0.45ml (5.65mmol) chloro-acetyl chloride, refluxed 18 hours, was cooled to room temperature and vacuum concentration.Residue diluted with water is used ethyl acetate extraction.Wash organic extract liquid then with water and use MgSO 4Dry.Vacuum concentration obtains oily matter, uses ethyl acetate on silica gel, and hexane (1.9) carries out chromatographic separation, obtains the light yellow oily title compound of 0.24g, solidifies during placement. 1H?NMR(250MHz，CDCl 3)δ8．1(m，2H)，7．5(m，3H)，4．8(s，2H)。
Prepare following compounds in the same manner:
5-chloromethyl-3-(2-methoxyphenyl)-1,2, the 4-oxadiazole, white is semi-solid, 1H NMR (250MHz, CDCl 3) δ 8.0 (dd, 2H), 7.5 (m, 1H), 7.0 (m, 2H), 4.8 (s, 2H), 4.0 (s, 3H).
5-chloromethyl-3-(4-methoxyphenyl)-1,2, the 4-oxadiazole, semisolid, 1H NMR (250MHz, CDCl 3) δ 8.0 (d, 2H), 7.0 (d, 2H), 4.8 (s, 2H), 4.0 (s, 3H); Mass spectrum m/e224 (M +).
5-chloromethyl-3-(4-chloro-phenyl-)-1,2, the 4-oxadiazole, semisolid, 1HNMR (250MHz, CDCl 3) δ 8.0 (d, 2H), 7.5 (d, 2H), 4.8 (s, 2H); Mass spectrum: m/e228 (M +).
Preparation 10
3-chloromethyl-5-(4-chloro-phenyl-)-1,2, the 4-oxadiazole
With 2-chloracetyl amidoxim (0.5g) and NaHCO 3(0.78g) solution in the 10ml anhydrous propanone was at room temperature handled 2 hours with 4-chloro-benzoyl chloride (0.58ml), and vacuum concentration is water-soluble and use ethyl acetate extraction.Merge organic layer, use MgSO 4Drying also is condensed into semisolid.This material is dissolved in the toluene (50ml) again, refluxed under nitrogen 15 hours, cools off and absorbs on the silica gel.Use ethyl acetate: hexane (1: 9) carries out chromatographic separation and obtains light yellow solid shape title product, mp 79-80 ℃.Mass spectrum m/e:228 (M +), 1H NMR (250MHz, CDCl 3) δ 8.1 (d, 2H), 7.5 (d, 2H), 4.7 (s, 2H).
Preparation 11
5-bromo-8-(4-methylpiperazine-1-yl) naphthalene-2-carboxylic acid 4-benzyl chloride base acid amides
Toward 8-(4-methylpiperazine-1-yl) naphthalene-2-carboxylic acid 4-benzyl chloride base acid amides (0.100g, 0.256mmol) and NaHCO 3(0.106g 1.26mmol) is added in 0.5ml CH in the solution in 2ml methyl alcohol 2Cl 2In bromine (26 μ l, 0.50mmol).30 minutes final vacuum evaporation reaction mixtures of stirring at room, resistates is with water treatment and use CH 2Cl 2Extraction.Organic extract liquid MgSO 4Drying also is condensed into yellow oil.Use methyl alcohol/dense ammonium hydroxide/methylene dichloride (2.0/0.2/97.9) chromatographic separation on silica gel to obtain slowly solidified oily title product of 0.040g (33%), mp103 ℃ (decomposition).Mass spectrum: m/e475 (M + 1), 395 (M +-Br), 1H NMR (CDCl 3) δ 8.6 (d, 1H), 8.3 (d, 1H), 7.8 (dd, 1H), 7.7 (d, 1H), 7.3 (s, 4H), 7.0 (d, 1H), 6.8 (t, 1H), 4.7 (d, 2H), 3.1 (bs, 4H), 2.7 (bs, 4H), 2.5 (s, 3H).
In the same manner 8-(4-methylpiperazine-1-yl) naphthalene-2-carboxylic acid 4-chloro-3-iodine benzyl acid amides is converted into 5-bromo-8-(4-methylpiperazine-1-yl) naphthalene-2-carboxylic acid 4-chloro-3-iodine benzyl acid amides, mp131 ℃ (decomposition) with 72% productive rate.Mass spectrum: m/e808,598.
1H?NMR(CDCl 3)δ8．7(d，1H)，8．2(d，1H)，7．5(m，2H)，7．7(d，1H)，7．4(d，1H)，7．3(dd，1H)，7．0(d，1H)，6．7(t，1H)，4．7(d，2H)，3．2(bs，4H)，2．7(bs，4H)，2．5?(s，3H)。

Claims (13)

  1. Figure 95193806000224
    Dotted line in its Chinese style III and the V is dispensable pair of key of arbitrariness, and as dotted line R when being two key 5Do not exist;
    A is 0,1 or 2;
    E is 0,1 or 2;
    M is the integer of 0-6;
    N is the integer of 1-3;
    P is the integer of 1-6;
    T is the integer of 0-3;
    R 2Be the substituting group and the R that on the either carbon atom of naphthalene nucleus, can form another root key 2Each appearance all be independently selected from hydrogen, fluorine, chlorine, bromine, iodine ,-CN ,-NO 2, (the C that arbitrariness replaces with 1-7 fluorine atom not essentially 1-C 6) alkyl, (the C that arbitrariness replaces with 1-7 fluorine atom not essentially 1-C 6) alkoxyl group, arbitrariness not essentially with the replacement of 1-7 fluorine atom-(C 1-C 6) alkylthio ,-OH ,-NR 20R 21,-CONR 20R 21With-CO 2R 20
    R 3Be hydrogen, (the C that arbitrariness replaces with 1-7 fluorine atom not essentially 1-C 10) alkyl ,-(CH 2) m-aryl ,-(CH 2) m-(C 5-C 7) cycloalkyl ,-(CH 2) n-R 27,-CO 2R 20Or arbitrariness is used the (C of 1-7 fluorine atom replacement not essentially 1-C 6) alkoxyl group; Wherein said-(CH 2) mBut the described aryl moiety arbitrariness of-aromatic yl group is independently selected from R with 1-3 not essentially 2The substituting group of any replaces in the listed substituting group; And wherein said-(CH 2) m-(C 5-C 7) described (C of group of naphthene base 5-C 7) but the cycloalkyl moiety arbitrariness is independently selected from R with 1-3 not essentially 2The substituting group of any replaces in the listed substituting group;
    R 4Be
    R 5Be hydrogen, (the C that arbitrariness replaces with 1-7 fluorine atom not essentially 1-C 6) alkyl, (the C that hydroxyl or arbitrariness replace with 1-7 fluorine atom not essentially 1-C 6) alkoxyl group; Wherein said (C 1-C 6But) alkyl also arbitrariness contain two keys of 1-3 root or three key not essentially;
    R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17And R 18Be selected from hydrogen independently of one another, bromine, chlorine, fluorine, the aryl, (C that arbitrariness replaces with 1-7 fluorine atom not essentially 1-C 6) alkyl, (the C that arbitrariness replaces with 1-7 fluorine atom not essentially 1-C 5) alkoxyl group, (the C that arbitrariness replaces with 1-7 fluorine atom not essentially 1-C 5) alkylthio, formyl radical ,-(C=O) R 20,-CN ,-OR 20,-NR 20R 21,-NR 20SO 2R 22,-NR 20CO 2R 22,-N=C-N (CH 3) 2,-S (O) eR 20,-SO 2NR 20R 21,-NO 2, aryl, (C 1-C 6) alkylaryl ,-(C=O) OR 20The NR of ,-(C=O) 20R 21, (C 1-C 6) alkyl, (C 1-C 6) alkenyl and (C 1-C 6) alkynyl;
    R 6And R 7, R 7And R 8, R 8And R 9, R 9And R 10, R 11And R 12, R 12And R 13, R 13And R 14, R 15And R 16, R 16And R 17And R 17And R 18Form 5-7 unit alkyl ring but lump together to arbitrariness, 6 yuan of aromatic rings, 5-7 unit has a N, the heteroatomic assorted alkyl ring of O or S, or 5-6 unit has 1 or 2 N, the heteroatomic hetero-aromatic ring of O or S;
    R 19Be hydrogen or (C 1-C 3) alkyl;
    R 20And R 21Each appearance all be hydrogen independently, (C 1-C 6) alkyl, aryl, or (C 1-C 6) alkylaryl, perhaps R 20And R 21Its arbitrary appearance all can form (C with the nitrogen-atoms that links to each other with it when being connected in same nitrogen-atoms 4-C 7) the alkyl ring;
    R 22Be (C 1-C 6) alkyl, aryl, or (C 1-C 6) alkylaryl;
    A, B, D, E and F are C independently of one another, N, or (C=O);
    G, I, J and K are C independently of one another, N, and O, S or (C=O), condition is that every ring has an O at the most, (C=O) or S;
    L and Z are C or N, wherein R independently of one another 18When being N, Z do not exist;
    M is C, N or (C=O), wherein R 19When being C=O, M do not exist;
    R 23And R 24Be independently selected from hydrogen, arbitrariness not essentially with the replacement of 1-7 fluorine atom-(C 1-C 6) alkyl, and when p greater than 1 the time, R 23And R 24Be selected from any other R independently of one another 23Or R 24
    R 25And R 26Be independently selected from hydrogen, arbitrariness not essentially with the replacement of 1-7 fluorine atom-(C 1-C 6) alkyl, and when t greater than 1 the time, R 25And R 26Be selected from any other R independently of one another 25Or R 26
    R 27For-OR 20,-C (=O) NR 20R 21,-C (=O) OR 20,-CN ,-NR 20C (=O) R 21,-O (C=O) R 20
    Dotted line represents that two key arbitrarinesses exist not essentially; With
    The aryl moiety of above-mentioned aryl and abovementioned alkyl aryl is independently selected from phenyl, naphthyl, the naphthyl that replaces and the phenyl of replacement, the naphthyl of wherein said replacement and the phenyl of replacement can be independently selected from (the C that arbitrariness replaces with 1-3 fluorine atom not essentially with 1-3 1-C 4) alkyl, halogen, hydroxyl, cyano group, the carboxamido, (C that nitro and arbitrariness replace with 1-3 fluorine atom not essentially 1-C 4) group of alkoxyl group replaces.
  2. 2. according to a kind of compound of claim 1, R wherein 1Be
    Figure 95193806000526
    P is 1, and t is 0, R 2, R 23And R 24Respectively be hydrogen.
  3. 3. according to a kind of compound of claim 2, R wherein 4Be pyridine, triazole, imidazo (4,5-b) pyridine, imidazoles-2-ketone (4,5-b) pyridine or benzoglyoxaline (benzamidazole).
  4. 4. according to a kind of compound of claim 2, R wherein 4Be to be selected from 1,2,4-oxadiazole base, 1,2,4-thiadiazolyl group, 1,3,5-oxadiazole base and 1,3,5 yuan of heterocycles of 5-thiadiazolyl group.
  5. 5. according to a kind of compound of claim 1,
    Figure 95193806000527
    P is 1, and t is 0, R 2, R 23And R 24Respectively be hydrogen.
  6. 6. according to a kind of compound of claim 1, P is 1, and t is 0, R 2, R 23And R 24Respectively be hydrogen.
  7. 7. according to a kind of compound of claim 1, R wherein 1Be
    Figure 95193806000629
    P is 1, and t is 0, R 2, R 23And R 24Respectively be hydrogen.
  8. 8. the compound of claim 1, described compound is selected from:
    1-{7-(5-(2-methoxyphenyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate;
    1-(7-(the 5-tertiary butyl-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl)-4-methylpiperazine hydrochloride dihydrate;
    1-methyl-4-(7-(3-phenyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl) piperazine dihydrochloride semihydrate;
    1-methyl-4-(7-(5-phenyl-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl) piperazine;
    1-{7-(5-(3-methoxyphenyl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate;
    1-{7-(5-(3,5-dimethyl isoxazole-4-yl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride hydrate;
    1-{7-(3-(4-methoxyphenyl)-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl }-4-methylpiperazine dihydrochloride semihydrate;
    2-(8-(1-methyl piperidine-4-yl) naphthalene-2-base oxygen base) pyrimidine;
    1-methyl-4-(7-(3-phenyl-(1,2,4 〕 oxadiazole-5-ylmethoxy) naphthalene-1-yl) piperidines; With
    4-{7-(5-(3,5-dimethyl isoxazole-4-yl)-(1,2,4 〕 oxadiazole-3-ylmethoxy) naphthalene-1-yl }-the 1-methyl piperidine.
  9. 9. a pharmaceutical composition is used for being selected from following disease in Mammals treatment or prevention: hypertension, depression, extensive anxiety disorder, phobia, catatonic syndrome after the wound, the avoidant personality is not normal, sexual disorder, eating disorder, fat, the chemical dependency, bunch headache, migraine, pain, presenile dementia, obsessive-compulsive disorder, Phobias, the memory disease, Parkinson's disease, endocrine regulation, vasospasm, gastrointestinal tract disease and chronic paroxysmal hemicrania and the headache relevant with vascular disease, said composition comprise compound and a kind of pharmaceutically acceptable carrier of the claim 1 that can effectively treat or prevent this kind disease amount.
  10. 10. pharmaceutical composition, be used for the treatment of or preventing disease, these treatment of diseases or prevention promote that by the serotoninergic nerve conduction of enhanced said composition comprises compound and a kind of pharmaceutically acceptable carrier of the claim 1 that can effectively treat or prevent this kind disease amount.
  11. 11. according to the pharmaceutical composition of claim 9, said composition comprises can effectively be resisted or compound and a kind of pharmaceutically acceptable carrier of the claim 1 of exciting 5-hydroxytryptamine receptor amount.
  12. 12. according to the pharmaceutical composition of claim 10, said composition is used for Mammals and comprises and can effectively resist or compound and a kind of pharmaceutically acceptable salt of the claim 1 of exciting 5-hydroxytryptamine receptor amount.
  13. 13. a pharmaceutical composition is used in Mammals treatment or preventing disease, these treatment of diseases or prevention promote that by the serotoninergic nerve conduction of enhanced said composition comprises:
    A) a kind of pharmaceutically acceptable carrier;
    B) a kind of compound of claim 1; With
    C) a kind of 5-HT reuptake inhibitor or its pharmaceutically acceptable salt;
    Wherein the amount of each active compound should make this combination effectively treat or prevent this kind disease.
CN95193806A 1994-06-29 1995-05-18 Aryl and heteroaryl alkoxynaphtalene derivatives Expired - Fee Related CN1064350C (en)

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